Hot off the presses! Nov 01 Nat Genet

The Nov 01 issue of the Nat Genet is now up on Pubget (About Nat Genet): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Discussing standards
  - Nat Genet 42(11):915 (2010)
  Nature Genetics | Editorial Discussing standards Journal name:Nature GeneticsVolume: 42 ,Page:915Year published:(2010)DOI:doi:10.1038/ng1110-915Published online27 October 2010 Whereas plans for data generation and public release can be agreed upon between data producers and their funders, community standards for the reporting, analysis and publication of high throughput data require wider discussion and broad consensus. View full text Additional data
• The Archon Genomics X PRIZE for whole human genome sequencing
  - Nat Genet 42(11):917-918 (2010)
  The $10 million Archon Genomics; X PRIZE (AGXP) was launched at the US National Academy of Sciences in 2006 to encourage the development of technologies to provide faster, cheaper and more complete whole human diploid genome sequences. The X PRIZE Foundation (hereafter 'Foundation') conceived the prize to educate the public and to raise awareness of the genomic technologies that will enable personalized genomic medicine.
• No evidence for lateral gene transfer between salmonids and schistosomes
  - Nat Genet 42(11):918-919 (2010)
  Nature Genetics | Correspondence No evidence for lateral gene transfer between salmonids and schistosomes * Christoph Grunau1christoph.grunau@univ-perp.fr Search for this author in: * NPG journals * PubMed * Google Scholar * Járôme Boissier1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 42 ,Pages:918–919Year published:(2010)DOI:doi:10.1038/ng1110-918Published online27 October 2010 To the Editor: A study published in this journal concluded that lateral gene transfer occurred from salmonid fish to two Schistosome species1. The deduction of gene transfer was based on the analysis of an expressed sequence tag library for Schistosoma japonicum (Adult SjC 7/94, GenBank accession number BU712912) and on PCR of genomic DNA and cDNA of Schistosoma mansoni and S. japonicum. Researchers in this study identified salmon transposon-like sequences in schistosomes, and these sequences were deposited in GenBank as schistosome-specific, salmon-like repeats (GenBank accession numbers AY834394–AY834403), stimulating considerable interest in the study's evolutionary implications2, 3, 4. Modern Schistosomatidae are parasitic helminths of mammals and birds, and the proximity to fish sufficient for gene transfer would require re-evaluation of the ecological and evolutionary history of these blood flukes. We here find no evidence for the proposed transfer of repetitive sequences from salm! onids to S. mansoni and S. japonicum. View full text Accession codes * Accession codes * Author information * Supplementary information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Referenced accessions Entrez Nucleotide * BU712912 * AY834394 * AY834403 * AY834402 * AY834401 * AY834399 * AY834397 * AY834395 * BU711870.1 Author information * Accession codes * Author information * Supplementary information Affiliations * CNRS/University of Perpignan Via Domitia, Center for Tropical and Mediterranean Biology and Ecology (UMR5244), Perpignan, France. * Christoph Grunau & * Járôme Boissier Contributions C.G. and J.B. designed the experiment and wrote the manuscript. C.G. performed the experimental work and the data analysis. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Christoph Grunau (christoph.grunau@univ-perp.fr) Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Figure, Tables and Note (2.2M) Supplementary Note, Supplementary Tables 1 and 2 and Supplementary Figure 1 Additional data
• Marker papers and data citation
  - Nat Genet 42(11):919 (2010)
  Thank you for your recent editorial describing an effort, initiated by the International Funders Forum, to develop a robust marker paper procedure that will provide the user community with important information about community resource projects. The concept of marker papers was originally developed at a data release meeting in 2003 (the 'Fort Lauderdale meeting').
• Lack of evidence for DNA methylation of Invader4 retroelements in Drosophila and implications for Dnmt2-mediated epigenetic regulation
  - Nat Genet 42(11):920-921 (2010)
  Nature Genetics | Correspondence Lack of evidence for DNA methylation of Invader4 retroelements in Drosophila and implications for Dnmt2-mediated epigenetic regulation * Matthias Schaefer1 Search for this author in: * NPG journals * PubMed * Google Scholar * Frank Lyko1f.lyko@dkfz.de Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 42 ,Pages:920–921Year published:(2010)DOI:doi:10.1038/ng1110-920Published online27 October 2010 To the Editor: In a recent issue of Nature Genetics, Phalke et al.1 described a new pathway for transposon silencing and telomere integrity in Drosophila that depends on the DNA methyltransferase homolog Dnmt2. Dnmt2 proteins are the most conserved members of the DNA methyltransferase family, but their substrate specificity has been discussed controversially within the scientific community2. Previous observations include a weak and highly distributive DNA methyltransferase activity of human DNMT2 in cell-free assays3, spurious DNA methylation in Drosophila4 and highly specific transfer RNA (tRNA) methyltransferase activity for cytosine 38 of tRNAAsp in mice, flies and plants5. All these observations seemed difficult to reconcile with the processive DNA methyltransferase activity in every dinucleotide context, as observed by Phalke et al.1, at Drosophila Invader4 retroelements. Furthermore, a recent genome-wide bisulfite sequencing study concluded that transposons are unmethylated in variou! s invertebrates and, specifically, in 0–3-hour-old Drosophila embryos6. View full text Accession codes * Accession codes * Author information * Supplementary information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Referenced accessions GenBank * FBte0000292 Author information * Accession codes * Author information * Supplementary information Affiliations * Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany. * Matthias Schaefer & * Frank Lyko Contributions M.S. performed the DNA methylation analysis. M.S. and F.L. conceived the study and wrote the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Frank Lyko (f.lyko@dkfz.de) Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Table, Methods and Note (1.2M) Supplementary Methods, Supplementary Table 1 and Supplementary Note Additional data
• Reply to "Lack of evidence for DNA methylation of Invader4 retroelements in Drosophila and implications for Dnmt2-mediated epigenetic regulation"
  - Nat Genet 42(11):921 (2010)
  In their Correspondence regarding our work published in Nature Genetics1, Schaefer and Lyko argue that the processive DNA methyltransferase activity in every dinucleotide context at Invader4 retroelements that we observed is difficult to reconcile with other reports about the activity of DNMT2 in Drosophila. However, until now, no other studies specifically analyzed DNA methylation at Invader4 retroelements.
• A common mechanism for microcephaly
  - Nat Genet 42(11):923-924 (2010)
  New studies employing high-throughput parallel sequencing have revealed WDR62 mutations in individuals with microcephaly associated with a broad range of malformations of cortical development. These findings establish that WDR62 acts as a molecular link between proliferation and migration in neurogenesis.
• Glutamate receptors and learning and memory
  - Nat Genet 42(11):925-926 (2010)
  Glutamate receptors have long been implicated in neurological processes underpinning learning and memory. A new study now shows that mutations in genes encoding glutamate receptor subunits can cause variable neurodevelopmental phenotypes including intellectual disability and epilepsy.
• Genome-wide association studies coming of age in rice
  - Nat Genet 42(11):926-927 (2010)
  A new study reports the next-generation sequencing of 517 rice genomes, each to approximately onefold coverage. By leveraging sequence information across rice lines and by imputing missing genotypes, a haplotype map (HapMap) was constructed and used for genome-wide association studies in this major crop.
• Research highlights
  - Nat Genet 42(11):929 (2010)
  
• Whole-genome sequencing and comprehensive variant analysis of a Japanese individual using massively parallel sequencing
  - Nat Genet 42(11):931-936 (2010)
  Nature Genetics | Article Whole-genome sequencing and comprehensive variant analysis of a Japanese individual using massively parallel sequencing * Akihiro Fujimoto1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Hidewaki Nakagawa1hidewaki@ims.u-tokyo.ac.jp Search for this author in: * NPG journals * PubMed * Google Scholar * Naoya Hosono1 Search for this author in: * NPG journals * PubMed * Google Scholar * Kaoru Nakano1 Search for this author in: * NPG journals * PubMed * Google Scholar * Tetsuo Abe1 Search for this author in: * NPG journals * PubMed * Google Scholar * Keith A Boroevich1 Search for this author in: * NPG journals * PubMed * Google Scholar * Masao Nagasaki3 Search for this author in: * NPG journals * PubMed * Google Scholar * Rui Yamaguchi3 Search for this author in: * NPG journals * PubMed * Google Scholar * Tetsuo Shibuya3 Search for this author in: * NPG journals * PubMed * Google Scholar * Michiaki Kubo1 Search for this author in: * NPG journals * PubMed * Google Scholar * Satoru Miyano2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Yusuke Nakamura1, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Tatsuhiko Tsunoda1, 2tsunoda@src.riken.jp Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 42 ,Pages:931–936Year published:(2010)DOI:doi:10.1038/ng.691Received18 February 2010Accepted10 September 2010Published online24 October 2010 Abstract * Abstract * Accession codes * Author information * Supplementary information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg We report the analysis of a Japanese male using high-throughput sequencing to ×40 coverage. More than 99% of the sequence reads were mapped to the reference human genome. Using a Bayesian decision method, we identified 3,132,608 single nucleotide variations (SNVs). Comparison with six previously reported genomes revealed an excess of singleton nonsense and nonsynonymous SNVs, as well as singleton SNVs in conserved non-coding regions. We also identified 5,319 deletions smaller than 10 kb with high accuracy, in addition to copy number variations and rearrangements. De novo assembly of the unmapped sequence reads generated around 3 Mb of novel sequence, which showed high similarity to non-reference human genomes and the human herpesvirus 4 genome. Our analysis suggests that considerable variation remains undiscovered in the human genome and that whole-genome sequencing is an invaluable tool for obtaining a complete understanding of human genetic variation. View full text Figures at a glance * Figure 1: Allelic frequency spectrum of seven genomes. () Frequency spectrum of SNVs of seven genomes. () Frequency spectrum of SNVs of seven genomes. PhastCon score >0.5 indicates conserved noncoding (light blue); phastCon score ≤0.5 represents less-conserved noncoding (pink). * Figure 2: Distribution of the number of SNVs within 1-Mb windows of seven individuals. See key for list of individual sequences. () Chromosome 1. () Chromosome 6. () Chromosome X. Scale bars indicate number of SNVs. * Figure 3: Identification of deletions. () An example of a homozygous deletion. Representation of mapped read pairs (gray and blue bars) and read depth (black dots) surrounding a homozygous deletion candidate region (pink shaded area). Gray bars show mapping locations of read pairs with expected fragment sizes; blue bars show mapping locations of read pairs with larger than expected fragment sizes (> average + 3 s.d.). () An example of a heterozygous deletion. () Examples of PCR validation for deletion candidates. Lanes 1–5 and 6–10 were homozygous and heterozygous candidates, respectively. Expected sizes of each PCR fragment (deletion/without deletion) were: lane 1: 118/498 bp; lane 2: 98/388 bp; lane 3: 147/476 bp; lane 4: 144/435 bp; lane 5: 133/454 bp; lane 6: 147/571 bp; lane 7: 122/540 bp; lane 8: 119/432 bp; lane 9: 136/582 bp; and lane 10: 112/529 bp. * Figure 4: De novo assembly of unmapped reads. () Comparison of contigs generated by ABySS (violet), SOAPdenovo (yellow) and Velvet (green). Contigs that were aligned with more than 90% identity were considered shared contigs. () Identification of contigs by ABySS showing the proportion of the total length represented by each category. () Identification of contigs by SOAPdenovo. () Identification of contigs by Velvet. Hs build36.3, human genome build 36; Hs GRCh37, human genome GRCh37; Hs Alt, human genome alternative assemblies (Celera and HuRef); Hs other, other human sequences in the NCBI database; Herpesvirus 4, human herpesvirus 4. Accession codes * Abstract * Accession codes * Author information * Supplementary information Referenced accessions DNA Data Bank of Japan * DRA000222 Author information * Abstract * Accession codes * Author information * Supplementary information Affiliations * Center for Genomic Medicine, RIKEN, Tsurumi, Yokohama, Japan. * Akihiro Fujimoto, * Hidewaki Nakagawa, * Naoya Hosono, * Kaoru Nakano, * Tetsuo Abe, * Keith A Boroevich, * Michiaki Kubo, * Yusuke Nakamura & * Tatsuhiko Tsunoda * Data Analysis Fusion Team, Computational Science Research Program, RIKEN, Tokyo, Japan. * Akihiro Fujimoto, * Satoru Miyano & * Tatsuhiko Tsunoda * Human Genome Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan. * Masao Nagasaki, * Rui Yamaguchi, * Tetsuo Shibuya, * Satoru Miyano & * Yusuke Nakamura Contributions H.N., Y.N., A.F. and T.T. designed the study. A.F., T.A., M.N., K.A.B. and R.Y. performed computational analyses. A.F., T.T., H.N. and K.A.B. wrote the manuscript. K.N. performed sequencing. N.H., A.F. and K.N. performed validation experiments. H.N. and T.T. obtained funding for the study. T.T., H.N., T.S., S.M. and M.K. advised on data analysis. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Tatsuhiko Tsunoda (tsunoda@src.riken.jp) or * Hidewaki Nakagawa (hidewaki@ims.u-tokyo.ac.jp) Supplementary information * Abstract * Accession codes * Author information * Supplementary information Other * Supplementary Table 2 (600K) List of non-3n deletions in coding regions * Supplementary Table 3 (416K) List of deletions detected by distance between paired reads and read depth * Supplementary Table 4 (68K) List of copy number gains * Supplementary Table 5 (56K) List of copy number losses PDF files * Supplementary Text and Figures (11M) Supplementary Figures 1–24 and Supplementary Tables 1,6–8 Additional data
• Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
  - Nat Genet 42(11):937-948 (2010)
  Nature Genetics | Article Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index * Elizabeth K Speliotes1, 2, 250 Search for this author in: * NPG journals * PubMed * Google Scholar * Cristen J Willer3, 250 Search for this author in: * NPG journals * PubMed * Google Scholar * Sonja I Berndt4, 250 Search for this author in: * NPG journals * PubMed * Google Scholar * Keri L Monda5, 250 Search for this author in: * NPG journals * PubMed * Google Scholar * Gudmar Thorleifsson6, 250 Search for this author in: * NPG journals * PubMed * Google Scholar * Anne U Jackson3 Search for this author in: * NPG journals * PubMed * Google Scholar * Hana Lango Allen7 Search for this author in: * NPG journals * PubMed * Google Scholar * Cecilia M Lindgren8, 9 Search for this author in: * NPG journals * PubMed * Google Scholar * Jian'an Luan10 Search for this author in: * NPG journals * PubMed * Google Scholar * Reedik Mägi8 Search for this author in: * NPG journals * PubMed * Google Scholar * Joshua C Randall8 Search for this author in: * NPG journals * PubMed * Google Scholar * Sailaja Vedantam1, 11 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas W Winkler12 Search for this author in: * NPG journals * PubMed * Google Scholar * Lu Qi13, 14 Search for this author in: * NPG journals * PubMed * Google Scholar * Tsegaselassie Workalemahu13 Search for this author in: * NPG journals * PubMed * Google Scholar * Iris M Heid12, 15 Search for this author in: * NPG journals * PubMed * Google Scholar * Valgerdur Steinthorsdottir6 Search for this author in: * NPG journals * PubMed * Google Scholar * Heather M Stringham3 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael N Weedon7 Search for this author in: * NPG journals * PubMed * Google Scholar * Eleanor Wheeler16 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew R Wood7 Search for this author in: * NPG journals * PubMed * Google Scholar * Teresa Ferreira8 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert J Weyant3 Search for this author in: * NPG journals * PubMed * Google Scholar * Ayellet V Segrè17, 18, 19 Search for this author in: * NPG journals * PubMed * Google Scholar * Karol Estrada20, 21, 22 Search for this author in: * NPG journals * PubMed * Google Scholar * Liming Liang23, 24 Search for this author in: * NPG journals * PubMed * Google Scholar * James Nemesh18 Search for this author in: * NPG journals * PubMed * Google Scholar * Ju-Hyun Park4 Search for this author in: * NPG journals * PubMed * Google Scholar * Stefan Gustafsson25 Search for this author in: * NPG journals * PubMed * Google Scholar * Tuomas O Kilpeläinen10 Search for this author in: * NPG journals * PubMed * Google Scholar * Jian Yang26 Search for this author in: * NPG journals * PubMed * Google Scholar * Nabila Bouatia-Naji27, 28 Search for this author in: * NPG journals * PubMed * Google Scholar * Tõnu Esko29, 30, 31, 29, 30, 31 Search for this author in: * NPG journals * PubMed * Google Scholar * Mary F Feitosa32 Search for this author in: * NPG journals * PubMed * Google Scholar * Zoltán Kutalik33, 34 Search for this author in: * NPG journals * PubMed * Google Scholar * Massimo Mangino35 Search for this author in: * NPG journals * PubMed * Google Scholar * Soumya Raychaudhuri18, 36 Search for this author in: * NPG journals * PubMed * Google Scholar * Andre Scherag37 Search for this author in: * NPG journals * PubMed * Google Scholar * Albert Vernon Smith38, 39 Search for this author in: * NPG journals * PubMed * Google Scholar * Ryan Welch3 Search for this author in: * NPG journals * PubMed * Google Scholar * Jing Hua Zhao10 Search for this author in: * NPG journals * PubMed * Google Scholar * Katja K Aben40 Search for this author in: * NPG journals * PubMed * Google Scholar * Devin M Absher41 Search for this author in: * NPG journals * PubMed * Google Scholar * Najaf Amin20 Search for this author in: * NPG journals * PubMed * Google Scholar * Anna L Dixon42 Search for this author in: * NPG journals * PubMed * Google Scholar * Eva Fisher43 Search for this author in: * NPG journals * PubMed * Google Scholar * Nicole L Glazer44, 45 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael E Goddard46, 47 Search for this author in: * NPG journals * PubMed * Google Scholar * Nancy L Heard-Costa48 Search for this author in: * NPG journals * PubMed * Google Scholar * Volker Hoesel49 Search for this author in: * NPG journals * PubMed * Google Scholar * Jouke-Jan Hottenga50 Search for this author in: * NPG journals * PubMed * Google Scholar * Åsa Johansson51, 52 Search for this author in: * NPG journals * PubMed * Google Scholar * Toby Johnson33, 34, 53, 54 Search for this author in: * NPG journals * PubMed * Google Scholar * Shamika Ketkar32 Search for this author in: * NPG journals * PubMed * Google Scholar * Claudia Lamina15, 55 Search for this author in: * NPG journals * PubMed * Google Scholar * Shengxu Li10 Search for this author in: * NPG journals * PubMed * Google Scholar * Miriam F Moffatt56 Search for this author in: * NPG journals * PubMed * Google Scholar * Richard H Myers57 Search for this author in: * NPG journals * PubMed * Google Scholar * Narisu Narisu58 Search for this author in: * NPG journals * PubMed * Google Scholar * John R B Perry7 Search for this author in: * NPG journals * PubMed * Google Scholar * Marjolein J Peters21, 22 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Preuss59 Search for this author in: * NPG journals * PubMed * Google Scholar * Samuli Ripatti60, 61 Search for this author in: * NPG journals * PubMed * Google Scholar * Fernando Rivadeneira20, 21, 22 Search for this author in: * NPG journals * PubMed * Google Scholar * Camilla Sandholt62 Search for this author in: * NPG journals * PubMed * Google Scholar * Laura J Scott3 Search for this author in: * NPG journals * PubMed * Google Scholar * Nicholas J Timpson63 Search for this author in: * NPG journals * PubMed * Google Scholar * Jonathan P Tyrer64 Search for this author in: * NPG journals * PubMed * Google Scholar * Sophie van Wingerden20 Search for this author in: * NPG journals * PubMed * Google Scholar * Richard M Watanabe65, 66 Search for this author in: * NPG journals * PubMed * Google Scholar * Charles C White67 Search for this author in: * NPG journals * PubMed * Google Scholar * Fredrik Wiklund25 Search for this author in: * NPG journals * PubMed * Google Scholar * Christina Barlassina68 Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel I Chasman69, 70 Search for this author in: * NPG journals * PubMed * Google Scholar * Matthew N Cooper71 Search for this author in: * NPG journals * PubMed * Google Scholar * John-Olov Jansson72 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert W Lawrence71 Search for this author in: * NPG journals * PubMed * Google Scholar * Niina Pellikka60, 61 Search for this author in: * NPG journals * PubMed * Google Scholar * Inga Prokopenko8, 9 Search for this author in: * NPG journals * PubMed * Google Scholar * Jianxin Shi4 Search for this author in: * NPG journals * PubMed * Google Scholar * Elisabeth Thiering15 Search for this author in: * NPG journals * PubMed * Google Scholar * Helene Alavere29 Search for this author in: * NPG journals * PubMed * Google Scholar * Maria T S Alibrandi73 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Almgren74 Search for this author in: * NPG journals * PubMed * Google Scholar * Alice M Arnold75, 76 Search for this author in: * NPG journals * PubMed * Google Scholar * Thor Aspelund38, 39 Search for this author in: * NPG journals * PubMed * Google Scholar * Larry D Atwood48 Search for this author in: * NPG journals * PubMed * Google Scholar * Beverley Balkau77, 78 Search for this author in: * NPG journals * PubMed * Google Scholar * Anthony J Balmforth79 Search for this author in: * NPG journals * PubMed * Google Scholar * Amanda J Bennett9 Search for this author in: * NPG journals * PubMed * Google Scholar * Yoav Ben-Shlomo80 Search for this author in: * NPG journals * PubMed * Google Scholar * Richard N Bergman66 Search for this author in: * NPG journals * PubMed * Google Scholar * Sven Bergmann33, 34 Search for this author in: * NPG journals * PubMed * Google Scholar * Heike Biebermann81 Search for this author in: * NPG journals * PubMed * Google Scholar * Alexandra I F Blakemore82 Search for this author in: * NPG journals * PubMed * Google Scholar * Tanja Boes37 Search for this author in: * NPG journals * PubMed * Google Scholar * Lori L Bonnycastle58 Search for this author in: * NPG journals * PubMed * Google Scholar * Stefan R Bornstein83 Search for this author in: * NPG journals * PubMed * Google Scholar * Morris J Brown84 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas A Buchanan66, 85 Search for this author in: * NPG journals * PubMed * Google Scholar * Fabio Busonero86 Search for this author in: * NPG journals * PubMed * Google Scholar * Harry Campbell87 Search for this author in: * NPG journals * PubMed * Google Scholar * Francesco P Cappuccio88 Search for this author in: * NPG journals * PubMed * Google Scholar * Christine Cavalcanti-Proença27, 28 Search for this author in: * NPG journals * PubMed * Google Scholar * Yii-Der Ida Chen89 Search for this author in: * NPG journals * PubMed * Google Scholar * Chih-Mei Chen15 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter S Chines58 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert Clarke90 Search for this author in: * NPG journals * PubMed * Google Scholar * Lachlan Coin91 Search for this author in: * NPG journals * PubMed * Google Scholar * John Connell92 Search for this author in: * NPG journals * PubMed * Google Scholar * Ian N M Day63 Search for this author in: * NPG journals * PubMed * Google Scholar * Martin den Heijer93, 94 Search for this author in: * NPG journals * PubMed * Google Scholar * Jubao Duan95 Search for this author in: * NPG journals * PubMed * Google Scholar * Shah Ebrahim96, 97 Search for this author in: * NPG journals * PubMed * Google Scholar * Paul Elliott91, 98 Search for this author in: * NPG journals * PubMed * Google Scholar * Roberto Elosua99 Search for this author in: * NPG journals * PubMed * Google Scholar * Gudny Eiriksdottir38 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael R Erdos58 Search for this author in: * NPG journals * PubMed * Google Scholar * Johan G Eriksson100, 101, 102, 103, 104 Search for this author in: * NPG journals * PubMed * Google Scholar * Maurizio F Facheris105, 106 Search for this author in: * NPG journals * PubMed * Google Scholar * Stephan B Felix107 Search for this author in: * NPG journals * PubMed * Google Scholar * Pamela Fischer-Posovszky108 Search for this author in: * NPG journals * PubMed * Google Scholar * Aaron R Folsom109 Search for this author in: * NPG journals * PubMed * Google Scholar * Nele Friedrich110 Search for this author in: * NPG journals * PubMed * Google Scholar * Nelson B Freimer111 Search for this author in: * NPG journals * PubMed * Google Scholar * Mao Fu112 Search for this author in: * NPG journals * PubMed * Google Scholar * Stefan Gaget27, 28 Search for this author in: * NPG journals * PubMed * Google Scholar * Pablo V Gejman95 Search for this author in: * NPG journals * PubMed * Google Scholar * Eco J C Geus50 Search for this author in: * NPG journals * PubMed * Google Scholar * Christian Gieger15 Search for this author in: * NPG journals * PubMed * Google Scholar * Anette P Gjesing62 Search for this author in: * NPG journals * PubMed * Google Scholar * Anuj Goel8, 113 Search for this author in: * NPG journals * PubMed * Google Scholar * Philippe Goyette114 Search for this author in: * NPG journals * PubMed * Google Scholar * Harald Grallert15 Search for this author in: * NPG journals * PubMed * Google Scholar * Jürgen Gräßler115 Search for this author in: * NPG journals * PubMed * Google Scholar * Danielle M Greenawalt116 Search for this author in: * NPG journals * PubMed * Google Scholar * Christopher J Groves9 Search for this author in: * NPG journals * PubMed * Google Scholar * Vilmundur Gudnason38, 39 Search for this author in: * NPG journals * PubMed * Google Scholar * Candace Guiducci1 Search for this author in: * NPG journals * PubMed * Google Scholar * Anna-Liisa Hartikainen117 Search for this author in: * NPG journals * PubMed * Google Scholar * Neelam Hassanali9 Search for this author in: * NPG journals * PubMed * Google Scholar * Alistair S Hall79 Search for this author in: * NPG journals * PubMed * Google Scholar * Aki S Havulinna118 Search for this author in: * NPG journals * PubMed * Google Scholar * Caroline Hayward119 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew C Heath120 Search for this author in: * NPG journals * PubMed * Google Scholar * Christian Hengstenberg121, 122 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew A Hicks105 Search for this author in: * NPG journals * PubMed * Google Scholar * Anke Hinney123 Search for this author in: * NPG journals * PubMed * Google Scholar * Albert Hofman20, 22 Search for this author in: * NPG journals * PubMed * Google Scholar * Georg Homuth124 Search for this author in: * NPG journals * PubMed * Google Scholar * Jennie Hui71, 125, 126 Search for this author in: * NPG journals * PubMed * Google Scholar * Wilmar Igl51 Search for this author in: * NPG journals * PubMed * Google Scholar * Carlos Iribarren127, 128 Search for this author in: * NPG journals * PubMed * Google Scholar * Bo Isomaa103, 129 Search for this author in: * NPG journals * PubMed * Google Scholar * Kevin B Jacobs130 Search for this author in: * NPG journals * PubMed * Google Scholar * Ivonne Jarick131 Search for this author in: * NPG journals * PubMed * Google Scholar * Elizabeth Jewell3 Search for this author in: * NPG journals * PubMed * Google Scholar * Ulrich John132 Search for this author in: * NPG journals * PubMed * Google Scholar * Torben Jørgensen133, 134 Search for this author in: * NPG journals * PubMed * Google Scholar * Pekka Jousilahti118 Search for this author in: * NPG journals * PubMed * Google Scholar * Antti Jula135 Search for this author in: * NPG journals * PubMed * Google Scholar * Marika Kaakinen136, 137 Search for this author in: * NPG journals * PubMed * Google Scholar * Eero Kajantie101, 138 Search for this author in: * NPG journals * PubMed * Google Scholar * Lee M Kaplan2, 70, 139 Search for this author in: * NPG journals * PubMed * Google Scholar * Sekar Kathiresan17, 18, 140, 141, 142 Search for this author in: * NPG journals * PubMed * Google Scholar * Johannes Kettunen60, 61 Search for this author in: * NPG journals * PubMed * Google Scholar * Leena Kinnunen143 Search for this author in: * NPG journals * PubMed * Google Scholar * Joshua W Knowles144 Search for this author in: * NPG journals * PubMed * Google Scholar * Ivana Kolcic145 Search for this author in: * NPG journals * PubMed * Google Scholar * Inke R König59 Search for this author in: * NPG journals * PubMed * Google Scholar * Seppo Koskinen118 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Kovacs146 Search for this author in: * NPG journals * PubMed * Google Scholar * Johanna Kuusisto147 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Kraft23, 24 Search for this author in: * NPG journals * PubMed * Google Scholar * Kirsti Kvaløy148 Search for this author in: * NPG journals * PubMed * Google Scholar * Jaana Laitinen149 Search for this author in: * NPG journals * PubMed * Google Scholar * Olivier Lantieri150 Search for this author in: * NPG journals * PubMed * Google Scholar * Chiara Lanzani73 Search for this author in: * NPG journals * PubMed * Google Scholar * Lenore J Launer151 Search for this author in: * NPG journals * PubMed * Google Scholar * Cecile Lecoeur27, 28 Search for this author in: * NPG journals * PubMed * Google Scholar * Terho Lehtimäki152 Search for this author in: * NPG journals * PubMed * Google Scholar * Guillaume Lettre114, 153 Search for this author in: * NPG journals * PubMed * Google Scholar * Jianjun Liu154 Search for this author in: * NPG journals * PubMed * Google Scholar * Marja-Liisa Lokki155 Search for this author in: * NPG journals * PubMed * Google Scholar * Mattias Lorentzon156 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert N Luben157 Search for this author in: * NPG journals * PubMed * Google Scholar * Barbara Ludwig83 Search for this author in: * NPG journals * PubMed * Google Scholar * MAGIC158 * Paolo Manunta73 Search for this author in: * NPG journals * PubMed * Google Scholar * Diana Marek33, 34 Search for this author in: * NPG journals * PubMed * Google Scholar * Michel Marre159, 160 Search for this author in: * NPG journals * PubMed * Google Scholar * Nicholas G Martin161 Search for this author in: * NPG journals * PubMed * Google Scholar * Wendy L McArdle162 Search for this author in: * NPG journals * PubMed * Google Scholar * Anne McCarthy163 Search for this author in: * NPG journals * PubMed * Google Scholar * Barbara McKnight75 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas Meitinger164, 165 Search for this author in: * NPG journals * PubMed * Google Scholar * Olle Melander166 Search for this author in: * NPG journals * PubMed * Google Scholar * David Meyre27, 28 Search for this author in: * NPG journals * PubMed * Google Scholar * Kristian Midthjell148 Search for this author in: * NPG journals * PubMed * Google Scholar * Grant W Montgomery167 Search for this author in: * NPG journals * PubMed * Google Scholar * Mario A Morken58 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew P Morris8 Search for this author in: * NPG journals * PubMed * Google Scholar * Rosanda Mulic168 Search for this author in: * NPG journals * PubMed * Google Scholar * Julius S Ngwa67 Search for this author in: * NPG journals * PubMed * Google Scholar * Mari Nelis29, 30, 31 Search for this author in: * NPG journals * PubMed * Google Scholar * Matt J Neville9 Search for this author in: * NPG journals * PubMed * Google Scholar * Dale R Nyholt169 Search for this author in: * NPG journals * PubMed * Google Scholar * Christopher J O'Donnell141, 170 Search for this author in: * NPG journals * PubMed * Google Scholar * Stephen O'Rahilly171 Search for this author in: * NPG journals * PubMed * Google Scholar * Ken K Ong10 Search for this author in: * NPG journals * PubMed * Google Scholar * Ben Oostra172 Search for this author in: * NPG journals * PubMed * Google Scholar * Guillaume Paré173 Search for this author in: * NPG journals * PubMed * Google Scholar * Alex N Parker174 Search for this author in: * NPG journals * PubMed * Google Scholar * Markus Perola60, 61 Search for this author in: * NPG journals * PubMed * Google Scholar * Irene Pichler105 Search for this author in: * NPG journals * PubMed * Google Scholar * Kirsi H Pietiläinen175, 176 Search for this author in: * NPG journals * PubMed * Google Scholar * Carl G P Platou148, 177 Search for this author in: * NPG journals * PubMed * Google Scholar * Ozren Polasek145, 178 Search for this author in: * NPG journals * PubMed * Google Scholar * Anneli Pouta117, 179 Search for this author in: * NPG journals * PubMed * Google Scholar * Suzanne Rafelt180 Search for this author in: * NPG journals * PubMed * Google Scholar * Olli Raitakari181, 182 Search for this author in: * NPG journals * PubMed * Google Scholar * Nigel W Rayner8, 9 Search for this author in: * NPG journals * PubMed * Google Scholar * Martin Ridderstråle166 Search for this author in: * NPG journals * PubMed * Google Scholar * Winfried Rief183 Search for this author in: * NPG journals * PubMed * Google Scholar * Aimo Ruokonen184 Search for this author in: * NPG journals * PubMed * Google Scholar * Neil R Robertson8, 9 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Rzehak15, 185 Search for this author in: * NPG journals * PubMed * Google Scholar * Veikko Salomaa118 Search for this author in: * NPG journals * PubMed * Google Scholar * Alan R Sanders95 Search for this author in: * NPG journals * PubMed * Google Scholar * Manjinder S Sandhu10, 16, 157 Search for this author in: * NPG journals * PubMed * Google Scholar * Serena Sanna86 Search for this author in: * NPG journals * PubMed * Google Scholar * Jouko Saramies186 Search for this author in: * NPG journals * PubMed * Google Scholar * Markku J Savolainen187 Search for this author in: * NPG journals * PubMed * Google Scholar * Susann Scherag123 Search for this author in: * NPG journals * PubMed * Google Scholar * Sabine Schipf110, 188 Search for this author in: * NPG journals * PubMed * Google Scholar * Stefan Schreiber189 Search for this author in: * NPG journals * PubMed * Google Scholar * Heribert Schunkert190 Search for this author in: * NPG journals * PubMed * Google Scholar * Kaisa Silander60, 61 Search for this author in: * NPG journals * PubMed * Google Scholar * Juha Sinisalo191 Search for this author in: * NPG journals * PubMed * Google Scholar * David S Siscovick45, 192 Search for this author in: * NPG journals * PubMed * Google Scholar * Jan H Smit193 Search for this author in: * NPG journals * PubMed * Google Scholar * Nicole Soranzo16, 35 Search for this author in: * NPG journals * PubMed * Google Scholar * Ulla Sovio91 Search for this author in: * NPG journals * PubMed * Google Scholar * Jonathan Stephens194, 195 Search for this author in: * NPG journals * PubMed * Google Scholar * Ida Surakka60, 61 Search for this author in: * NPG journals * PubMed * Google Scholar * Amy J Swift58 Search for this author in: * NPG journals * PubMed * Google Scholar * Mari-Liis Tammesoo29 Search for this author in: * NPG journals * PubMed * Google Scholar * Jean-Claude Tardif114, 153 Search for this author in: * NPG journals * PubMed * Google Scholar * Maris Teder-Laving30, 31 Search for this author in: * NPG journals * PubMed * Google Scholar * Tanya M Teslovich3 Search for this author in: * NPG journals * PubMed * Google Scholar * John R Thompson196, 197 Search for this author in: * NPG journals * PubMed * Google Scholar * Brian Thomson1 Search for this author in: * NPG journals * PubMed * Google Scholar * Anke Tönjes198, 199 Search for this author in: * NPG journals * PubMed * Google Scholar * Tiinamaija Tuomi103, 200, 201 Search for this author in: * NPG journals * PubMed * Google Scholar * Joyce B J van Meurs20, 21, 22 Search for this author in: * NPG journals * PubMed * Google Scholar * Gert-Jan van Ommen202, 203 Search for this author in: * NPG journals * PubMed * Google Scholar * Vincent Vatin27, 28 Search for this author in: * NPG journals * PubMed * Google Scholar * Jorma Viikari204 Search for this author in: * NPG journals * PubMed * Google Scholar * Sophie Visvikis-Siest205 Search for this author in: * NPG journals * PubMed * Google Scholar * Veronique Vitart119 Search for this author in: * NPG journals * PubMed * Google Scholar * Carla I G Vogel123 Search for this author in: * NPG journals * PubMed * Google Scholar * Benjamin F Voight17, 18, 19 Search for this author in: * NPG journals * PubMed * Google Scholar * Lindsay L Waite41 Search for this author in: * NPG journals * PubMed * Google Scholar * Henri Wallaschofski110 Search for this author in: * NPG journals * PubMed * Google Scholar * G Bragi Walters6 Search for this author in: * NPG journals * PubMed * Google Scholar * Elisabeth Widen60 Search for this author in: * NPG journals * PubMed * Google Scholar * Susanna Wiegand81 Search for this author in: * NPG journals * PubMed * Google Scholar * Sarah H Wild87 Search for this author in: * NPG journals * PubMed * Google Scholar * Gonneke Willemsen50 Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel R Witte206 Search for this author in: * NPG journals * PubMed * Google Scholar * Jacqueline C Witteman20, 22 Search for this author in: * NPG journals * PubMed * Google Scholar * Jianfeng Xu207 Search for this author in: * NPG journals * PubMed * Google Scholar * Qunyuan Zhang32 Search for this author in: * NPG journals * PubMed * Google Scholar * Lina Zgaga145 Search for this author in: * NPG journals * PubMed * Google Scholar * Andreas Ziegler59 Search for this author in: * NPG journals * PubMed * Google Scholar * Paavo Zitting208 Search for this author in: * NPG journals * PubMed * Google Scholar * John P Beilby125, 126, 209 Search for this author in: * NPG journals * PubMed * Google Scholar * I Sadaf Farooqi171 Search for this author in: * NPG journals * PubMed * Google Scholar * Johannes Hebebrand123 Search for this author in: * NPG journals * PubMed * Google Scholar * Heikki V Huikuri210 Search for this author in: * NPG journals * PubMed * Google Scholar * Alan L James126, 211 Search for this author in: * NPG journals * PubMed * Google Scholar * Mika Kähönen212 Search for this author in: * NPG journals * PubMed * Google Scholar * Douglas F Levinson213 Search for this author in: * NPG journals * PubMed * Google Scholar * Fabio Macciardi68, 214 Search for this author in: * NPG journals * PubMed * Google Scholar * Markku S Nieminen191 Search for this author in: * NPG journals * PubMed * Google Scholar * Claes Ohlsson156 Search for this author in: * NPG journals * PubMed * Google Scholar * Lyle J Palmer71, 126 Search for this author in: * NPG journals * PubMed * Google Scholar * Paul M Ridker69, 70 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Stumvoll198, 215 Search for this author in: * NPG journals * PubMed * Google Scholar * Jacques S Beckmann33, 216 Search for this author in: * NPG journals * PubMed * Google Scholar * Heiner Boeing43 Search for this author in: * NPG journals * PubMed * Google Scholar * Eric Boerwinkle217 Search for this author in: * NPG journals * PubMed * Google Scholar * Dorret I Boomsma50 Search for this author in: * NPG journals * PubMed * Google Scholar * Mark J Caulfield54 Search for this author in: * NPG journals * PubMed * Google Scholar * Stephen J Chanock4 Search for this author in: * NPG journals * PubMed * Google Scholar * Francis S Collins58 Search for this author in: * NPG journals * PubMed * Google Scholar * L Adrienne Cupples67 Search for this author in: * NPG journals * PubMed * Google Scholar * George Davey Smith63 Search for this author in: * NPG journals * PubMed * Google Scholar * Jeanette Erdmann190 Search for this author in: * NPG journals * PubMed * Google Scholar * Philippe Froguel27, 28, 82 Search for this author in: * NPG journals * PubMed * Google Scholar * Henrik Grönberg25 Search for this author in: * NPG journals * PubMed * Google Scholar * Ulf Gyllensten51 Search for this author in: * NPG journals * PubMed * Google Scholar * Per Hall25 Search for this author in: * NPG journals * PubMed * Google Scholar * Torben Hansen62, 218 Search for this author in: * NPG journals * PubMed * Google Scholar * Tamara B Harris151 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew T Hattersley7 Search for this author in: * NPG journals * PubMed * Google Scholar * Richard B Hayes219 Search for this author in: * NPG journals * PubMed * Google Scholar * Joachim Heinrich15 Search for this author in: * NPG journals * PubMed * Google Scholar * Frank B Hu13, 14, 23 Search for this author in: * NPG journals * PubMed * Google Scholar * Kristian Hveem148 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas Illig15 Search for this author in: * NPG journals * PubMed * Google Scholar * Marjo-Riitta Jarvelin91, 136, 137, 179 Search for this author in: * NPG journals * PubMed * Google Scholar * Jaakko Kaprio60, 175, 220 Search for this author in: * NPG journals * PubMed * Google Scholar * Fredrik Karpe9, 221 Search for this author in: * NPG journals * PubMed * Google Scholar * Kay-Tee Khaw157 Search for this author in: * NPG journals * PubMed * Google Scholar * Lambertus A Kiemeney40, 93, 222 Search for this author in: * NPG journals * PubMed * Google Scholar * Heiko Krude81 Search for this author in: * NPG journals * PubMed * Google Scholar * Markku Laakso147 Search for this author in: * NPG journals * PubMed * Google Scholar * Debbie A Lawlor63 Search for this author in: * NPG journals * PubMed * Google Scholar * Andres Metspalu29, 30, 31 Search for this author in: * NPG journals * PubMed * Google Scholar * Patricia B Munroe54 Search for this author in: * NPG journals * PubMed * Google Scholar * Willem H Ouwehand16, 194, 195 Search for this author in: * NPG journals * PubMed * Google Scholar * Oluf Pedersen62, 223, 224 Search for this author in: * NPG journals * PubMed * Google Scholar * Brenda W Penninx193, 225, 226 Search for this author in: * NPG journals * PubMed * Google Scholar * Annette Peters15 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter P Pramstaller105, 106, 227 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas Quertermous144 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas Reinehr228 Search for this author in: * NPG journals * PubMed * Google Scholar * Aila Rissanen176 Search for this author in: * NPG journals * PubMed * Google Scholar * Igor Rudan87, 168 Search for this author in: * NPG journals * PubMed * Google Scholar * Nilesh J Samani180, 196 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter E H Schwarz229 Search for this author in: * NPG journals * PubMed * Google Scholar * Alan R Shuldiner112, 230 Search for this author in: * NPG journals * PubMed * Google Scholar * Timothy D Spector35 Search for this author in: * NPG journals * PubMed * Google Scholar * Jaakko Tuomilehto143, 231, 232 Search for this author in: * NPG journals * PubMed * Google Scholar * Manuela Uda86 Search for this author in: * NPG journals * PubMed * Google Scholar * André Uitterlinden20, 21, 22 Search for this author in: * NPG journals * PubMed * Google Scholar * Timo T Valle143 Search for this author in: * NPG journals * PubMed * Google Scholar * Martin Wabitsch108 Search for this author in: * NPG journals * PubMed * Google Scholar * Gérard Waeber233 Search for this author in: * NPG journals * PubMed * Google Scholar * Nicholas J Wareham10 Search for this author in: * NPG journals * PubMed * Google Scholar * Hugh Watkins8, 113 Search for this author in: * NPG journals * PubMed * Google Scholar * on behalf of Procardis Consortium * James F Wilson87 Search for this author in: * NPG journals * PubMed * Google Scholar * Alan F Wright119 Search for this author in: * NPG journals * PubMed * Google Scholar * M Carola Zillikens21, 22 Search for this author in: * NPG journals * PubMed * Google Scholar * Nilanjan Chatterjee4 Search for this author in: * NPG journals * PubMed * Google Scholar * Steven A McCarroll17, 18, 19 Search for this author in: * NPG journals * PubMed * Google Scholar * Shaun Purcell17, 234, 235 Search for this author in: * NPG journals * PubMed * Google Scholar * Eric E Schadt236, 237 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter M Visscher26 Search for this author in: * NPG journals * PubMed * Google Scholar * Themistocles L Assimes144 Search for this author in: * NPG journals * PubMed * Google Scholar * Ingrid B Borecki32, 238 Search for this author in: * NPG journals * PubMed * Google Scholar * Panos Deloukas16 Search for this author in: * NPG journals * PubMed * Google Scholar * Caroline S Fox239 Search for this author in: * NPG journals * PubMed * Google Scholar * Leif C Groop74 Search for this author in: * NPG journals * PubMed * Google Scholar * Talin Haritunians89 Search for this author in: * NPG journals * PubMed * Google Scholar * David J Hunter13, 14, 23 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert C Kaplan240 Search for this author in: * NPG journals * PubMed * Google Scholar * Karen L Mohlke241 Search for this author in: * NPG journals * PubMed * Google Scholar * Jeffrey R O'Connell112 Search for this author in: * NPG journals * PubMed * Google Scholar * Leena Peltonen16, 60, 61, 234, 242 Search for this author in: * NPG journals * PubMed * Google Scholar * David Schlessinger243 Search for this author in: * NPG journals * PubMed * Google Scholar * David P Strachan244 Search for this author in: * NPG journals * PubMed * Google Scholar * Cornelia M van Duijn20, 22 Search for this author in: * NPG journals * PubMed * Google Scholar * H-Erich Wichmann15, 185, 245 Search for this author in: * NPG journals * PubMed * Google Scholar * Timothy M Frayling7 Search for this author in: * NPG journals * PubMed * Google Scholar * Unnur Thorsteinsdottir6, 246 Search for this author in: * NPG journals * PubMed * Google Scholar * Gonçalo R Abecasis3 Search for this author in: * NPG journals * PubMed * Google Scholar * Inês Barroso16, 247 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Boehnke3, 250boehnke@umich.edu Search for this author in: * NPG journals * PubMed * Google Scholar * Kari Stefansson6, 246, 250kstefans@decode.is Search for this author in: * NPG journals * PubMed * Google Scholar * Kari E North5, 248, 250kari_north@unc.edu Search for this author in: * NPG journals * PubMed * Google Scholar * Mark I McCarthy8, 9, 221, 250mark.mccarthy@drl.ox.ac.uk Search for this author in: * NPG journals * PubMed * Google Scholar * Joel N Hirschhorn1, 11, 249, 250joelh@broadinstitute.org Search for this author in: * NPG journals * PubMed * Google Scholar * Erik Ingelsson25, 250erik.ingelsson@ki.se Search for this author in: * NPG journals * PubMed * Google Scholar * Ruth J F Loos10, 250ruth.loos@mrc-epid.cam.ac.uk Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 42 ,Pages:937–948Year published:(2010)DOI:doi:10.1038/ng.686Received13 May 2010Accepted15 September 2010Published online10 October 2010 Abstract * Abstract * Author information * Supplementary information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation. View full text Figures at a glance * Figure 1: Genome-wide association results for the BMI meta-analysis. () Manhattan plot showing the significance of association between all SNPs and BMI in the stage 1 meta-analysis, highlighting SNPs previously reported to show genome-wide significant association with BMI (blue), weight or waist circumference (green) and the 18 new regions described here (red). The 19 SNPs that reached genome-wide significance in stage 1 (13 previously reported and 6 new SNPs) are listed in Table 1. () Quantile-quantile plot of SNPs in the stage 1 meta-analysis (black) and after removing any SNPs within 1 Mb of the ten previously reported genome-wide significant hits for BMI (blue), after additionally excluding SNPs from the four loci for waist or weight (green), and after excluding SNPs from all 32 confirmed loci (red). The plot is abridged at the y axis (at P < 10−20) to better visualize the excess of small P values after excluding the 32 confirmed loci (Supplementary Fig. 3 shows the full-scale quantile-quantile plot). The shaded region is the 95% concen! tration band. () Plot of effect size (in inverse-normally transformed units (invBMI)) versus effect-allele frequency of newly identified and previously identified BMI variants after stage 1 and stage 2 meta-analysis, including the 10 previously identified BMI loci (blue), the 4 previously identified waist and weight loci (green) and the 18 newly identified BMI loci (blue). The dotted lines represent the minimum effect sizes that could be identified for a given effect-allele frequency with 80% (upper line), 50% (middle line) and 10% (lower line) power, assuming a sample size of 123,000 individuals and an α level of 5 × 10−8. * Figure 2: Combined impact of risk alleles on BMI and obesity. () Combined effect of risk alleles on average BMI in the population-based ARIC study (n = 8,120 individuals of European descent). For each individual, the number of 'best guess' replicated (n = 32) risk alleles from imputed data (0, 1 or 2) per SNP was weighted for its relative effect size estimated from the stage 2 data. Weighted risk alleles were summed for each individual, and the overall individual sum was rounded to the nearest integer to represent the individual's risk allele score (ranging from 16 to 44). Along the x axis, individuals in each risk allele category are shown (grouped as having ≤21 risk alleles and ≥38 risk alleles at the extremes), and the mean BMI (± s.e.m.) is plotted (y axis on right), with the line representing the regression of the mean BMI values across the risk-allele scores. The histogram (y axis on left) represents the number of individuals in each risk-score category. () The area under the ROC curve (AUC) of two different models predictin! g the risk of obesity (BMI ≥ 30 kg/m2) in the 8,120 genotyped individuals of European descent in the ARIC study. Model 1, represented by the solid line, includes age, age2 and sex (AUC = 0.515, P = 0.023 for difference from the null AUC = 0.50). Model 2, represented by the dashed line, includes age, age2, sex and the 32 confirmed BMI SNPs (AUC = 0.575, P < 10−5 for difference from the null AUC = 0.50). The difference between both AUCs is significant (P < 10−4). * Figure 3: Regional plots of selected replicating BMI loci with missense and CNV variants. SNPs are plotted by position on the chromosome against association with BMI (–log10P). The SNP name shown on the plot was the most significant SNP after the stage 1 meta-analysis. Estimated recombination rates (from HapMap) are plotted in cyan to reflect the local LD structure. The SNPs surrounding the most significant SNP are color coded to reflect their LD with this SNP (taken from pairwise r2 values from the HapMap CEU data). Genes, the position of exons and the direction of transcription from the UCSC genome browser are noted. Hashmarks represent SNP positions available in the meta-analysis. (–) Missense variants noted with their amino acid change for the gene listed above the plot. () Structural haplotypes and the BMI association signal in the GPRC5B region. A 21-kb deletion polymorphism was associated with four SNPs (r2 = 1.0) that comprise the best haplogroup associating with BMI. Plots were generated using LocusZoom (see URLs). * Figure 4: Phenotypic variance explained by common variants. () The variance explained is higher when SNPs not reaching genome-wide significance are included in the prediction model. The y axis represents the proportion of variance explained at different P value thresholds from the stage 1 meta-analysis. Results are given for three studies (Rotterdam Study II (RSII), Rotterdam Study III (RSIII), Queens Institute of Medical Research (QIMR)) which were not included in the meta-analysis, after exclusion of all samples from The Netherlands (for RSII and RSIII) and the United Kingdom (for QIMR) from the discovery analysis for this sub-analysis. The dotted line represents the weighted average of the explained variance of three validation sets. () Cumulative number of susceptibility loci expected to be discovered, including those we have already identified and others that have yet to be detected, by the expected percentage of phenotypic variation explained and the sample size required for a one-stage GWAS assuming a genomic control correctio! n is used. The projections are based on loci that achieved a significance level of P < 5 × 10−8 in the joint analysis of stage 1 and stage 2 and the distribution of their effect sizes in stage 2. The dotted red line corresponds to the expected phenotypic variance explained by the 22 loci that are expected to be discovered in a one-stage GWAS using the sample size of stage 1 of this study. * Figure 5: A second signal at the MC4R locus contributing to BMI. SNPs are plotted by position in a 1-Mb window of chromosome 18 against association with BMI (–log10P). () Plot highlighting the most significant SNP in the stage 1 meta-analysis. () Plot highlighting the most significant SNP after conditional analysis, where the model included the most strongly associated SNP as a covariate. Estimated recombination rates (from HapMap) are plotted in cyan to reflect the local LD structure. The SNPs surrounding the most significant SNP are color coded to reflect their LD with this SNP (taken from pairwise r2 values from the HapMap CEU database). Genes, exons and the direction of transcription from the UCSC genome browser are noted. Hashmarks at the top of the figure represent the positions of SNPs in the meta-analysis. Regional plots were generated using LocusZoom. Author information * Abstract * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Elizabeth K Speliotes, * Cristen J Willer, * Sonja I Berndt, * Keri L Monda, * Gudmar Thorleifsson, * Michael Boehnke, * Kari Stefansson, * Kari E North, * Mark I McCarthy, * Joel N Hirschhorn, * Erik Ingelsson & * Ruth J F Loos Affiliations * Metabolism Initiative and Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. * Elizabeth K Speliotes, * Sailaja Vedantam, * Candace Guiducci, * Brian Thomson & * Joel N Hirschhorn * Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA. * Elizabeth K Speliotes & * Lee M Kaplan * Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA. * Cristen J Willer, * Anne U Jackson, * Heather M Stringham, * Robert J Weyant, * Ryan Welch, * Laura J Scott, * Elizabeth Jewell, * Tanya M Teslovich, * Gonçalo R Abecasis & * Michael Boehnke * Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA. * Sonja I Berndt, * Ju-Hyun Park, * Jianxin Shi, * Stephen J Chanock & * Nilanjan Chatterjee * Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. * Keri L Monda & * Kari E North * deCODE Genetics, Reykjavik, Iceland. * Gudmar Thorleifsson, * Valgerdur Steinthorsdottir, * G Bragi Walters, * Unnur Thorsteinsdottir & * Kari Stefansson * Genetics of Complex Traits, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK. * Hana Lango Allen, * Michael N Weedon, * Andrew R Wood, * John R B Perry, * Andrew T Hattersley & * Timothy M Frayling * Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. * Cecilia M Lindgren, * Reedik Mägi, * Joshua C Randall, * Teresa Ferreira, * Inga Prokopenko, * Anuj Goel, * Andrew P Morris, * Nigel W Rayner, * Neil R Robertson, * Hugh Watkins & * Mark I McCarthy * Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK. * Cecilia M Lindgren, * Inga Prokopenko, * Amanda J Bennett, * Christopher J Groves, * Neelam Hassanali, * Matt J Neville, * Nigel W Rayner, * Neil R Robertson, * Fredrik Karpe & * Mark I McCarthy * Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. * Jian'an Luan, * Tuomas O Kilpeläinen, * Jing Hua Zhao, * Shengxu Li, * Ken K Ong, * Manjinder S Sandhu, * Nicholas J Wareham & * Ruth J F Loos * Divisions of Genetics and Endocrinology and Program in Genomics, Children's Hospital,Boston, Massachusetts, USA. * Sailaja Vedantam & * Joel N Hirschhorn * Regensburg University Medical Center, Department of Epidemiology and Preventive Medicine, Regensburg, Germany. * Thomas W Winkler & * Iris M Heid * Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA. * Lu Qi, * Tsegaselassie Workalemahu, * Frank B Hu & * David J Hunter * Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. * Lu Qi, * Frank B Hu & * David J Hunter * Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. * Iris M Heid, * Claudia Lamina, * Elisabeth Thiering, * Chih-Mei Chen, * Christian Gieger, * Harald Grallert, * Peter Rzehak, * Joachim Heinrich, * Thomas Illig, * Annette Peters & * H-Erich Wichmann * Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. * Eleanor Wheeler, * Manjinder S Sandhu, * Nicole Soranzo, * Willem H Ouwehand, * Panos Deloukas, * Leena Peltonen & * Inês Barroso * Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. * Ayellet V Segrè, * Sekar Kathiresan, * Benjamin F Voight, * Steven A McCarroll & * Shaun Purcell * Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. * Ayellet V Segrè, * James Nemesh, * Soumya Raychaudhuri, * Sekar Kathiresan, * Benjamin F Voight & * Steven A McCarroll * Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA. * Ayellet V Segrè, * Benjamin F Voight & * Steven A McCarroll * Department of Epidemiology, Erasmus Medical Center (MC), Rotterdam, The Netherlands. * Karol Estrada, * Najaf Amin, * Fernando Rivadeneira, * Sophie van Wingerden, * Albert Hofman, * Joyce B J van Meurs, * Jacqueline C Witteman, * André Uitterlinden & * Cornelia M van Duijn * Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. * Karol Estrada, * Marjolein J Peters, * Fernando Rivadeneira, * Joyce B J van Meurs, * André Uitterlinden & * M Carola Zillikens * Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, The Netherlands. * Karol Estrada, * Marjolein J Peters, * Fernando Rivadeneira, * Albert Hofman, * Joyce B J van Meurs, * Jacqueline C Witteman, * André Uitterlinden, * M Carola Zillikens & * Cornelia M van Duijn * Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. * Liming Liang, * Peter Kraft, * Frank B Hu & * David J Hunter * Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA. * Liming Liang & * Peter Kraft * Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. * Stefan Gustafsson, * Fredrik Wiklund, * Henrik Grönberg, * Per Hall & * Erik Ingelsson * Queensland Statistical Genetics Laboratory, Queensland Institute of Medical Research, Queensland, Australia. * Jian Yang & * Peter M Visscher * Centre National de la Recherche Scientifique (CNRS) UMR8199-IBL-Institut Pasteur de Lille, Lille, France. * Nabila Bouatia-Naji, * Christine Cavalcanti-Proença, * Stefan Gaget, * Cecile Lecoeur, * David Meyre, * Vincent Vatin & * Philippe Froguel * University Lille Nord de France, Lille, France. * Nabila Bouatia-Naji, * Christine Cavalcanti-Proença, * Stefan Gaget, * Cecile Lecoeur, * David Meyre, * Vincent Vatin & * Philippe Froguel * Estonian Genome Center, University of Tartu, Tartu, Estonia. * Tõnu Esko, * Helene Alavere, * Mari Nelis, * Mari-Liis Tammesoo & * Andres Metspalu * Estonian Biocenter, Tartu, Estonia. * Tõnu Esko, * Mari Nelis, * Maris Teder-Laving & * Andres Metspalu * Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. * Tõnu Esko, * Mari Nelis, * Maris Teder-Laving & * Andres Metspalu * Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA. * Mary F Feitosa, * Shamika Ketkar, * Qunyuan Zhang & * Ingrid B Borecki * Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland. * Zoltán Kutalik, * Toby Johnson, * Sven Bergmann, * Diana Marek & * Jacques S Beckmann * Swiss Institute of Bioinformatics, Lausanne, Switzerland. * Zoltán Kutalik, * Toby Johnson, * Sven Bergmann & * Diana Marek * Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. * Massimo Mangino, * Nicole Soranzo & * Timothy D Spector * Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. * Soumya Raychaudhuri * Institute for Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Essen, Germany. * Andre Scherag & * Tanja Boes * Icelandic Heart Association, Kopavogur, Iceland. * Albert Vernon Smith, * Thor Aspelund, * Gudny Eiriksdottir & * Vilmundur Gudnason * University of Iceland, Reykjavik, Iceland. * Albert Vernon Smith, * Thor Aspelund & * Vilmundur Gudnason * Comprehensive Cancer Center East, Nijmegen, The Netherlands. * Katja K Aben & * Lambertus A Kiemeney * Hudson Alpha Institute for Biotechnology, Huntsville, Alabama, USA. * Devin M Absher & * Lindsay L Waite * Department of Pharmacy and Pharmacology, University of Bath, Bath, UK. * Anna L Dixon * Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. * Eva Fisher & * Heiner Boeing * Department of Medicine, University of Washington, Seattle, Washington, USA. * Nicole L Glazer * Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA. * Nicole L Glazer & * David S Siscovick * University of Melbourne, Parkville, Australia. * Michael E Goddard * Department of Primary Industries, Melbourne, Victoria, Australia. * Michael E Goddard * Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA. * Nancy L Heard-Costa & * Larry D Atwood * Technical University Munich, Chair of Biomathematics, Garching, Germany. * Volker Hoesel * Department of Biological Psychology, Vrije Universiteit (VU) University Amsterdam, Amsterdam, The Netherlands. * Jouke-Jan Hottenga, * Eco J C Geus, * Gonneke Willemsen & * Dorret I Boomsma * Department of Genetics and Pathology, Rudbeck Laboratory, University of Uppsala, Uppsala, Sweden. * Åsa Johansson, * Wilmar Igl & * Ulf Gyllensten * Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway. * Åsa Johansson * Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK. * Toby Johnson * Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK. * Toby Johnson, * Mark J Caulfield & * Patricia B Munroe * Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria. * Claudia Lamina * National Heart and Lung Institute, Imperial College London, London, UK. * Miriam F Moffatt * Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA. * Richard H Myers * National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. * Narisu Narisu, * Lori L Bonnycastle, * Peter S Chines, * Michael R Erdos, * Mario A Morken, * Amy J Swift & * Francis S Collins * Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany. * Michael Preuss, * Inke R König & * Andreas Ziegler * Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. * Samuli Ripatti, * Niina Pellikka, * Johannes Kettunen, * Markus Perola, * Kaisa Silander, * Ida Surakka, * Elisabeth Widen, * Jaakko Kaprio & * Leena Peltonen * National Institute for Health and Welfare, Department of Chronic Disease Prevention, Unit of Public Health Genomics, Helsinki, Finland. * Samuli Ripatti, * Niina Pellikka, * Johannes Kettunen, * Markus Perola, * Kaisa Silander, * Ida Surakka & * Leena Peltonen * Hagedorn Research Institute, Gentofte, Denmark. * Camilla Sandholt, * Anette P Gjesing, * Torben Hansen & * Oluf Pedersen * MRC Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, Oakfield House, Bristol, UK. * Nicholas J Timpson, * Ian N M Day, * George Davey Smith & * Debbie A Lawlor * Department of Oncology, University of Cambridge, Cambridge, UK. * Jonathan P Tyrer * Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. * Richard M Watanabe * Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. * Richard M Watanabe, * Richard N Bergman & * Thomas A Buchanan * Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA. * Charles C White, * Julius S Ngwa & * L Adrienne Cupples * University of Milan, Department of Medicine, Surgery and Dentistry, Milano, Italy. * Christina Barlassina & * Fabio Macciardi * Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. * Daniel I Chasman & * Paul M Ridker * Harvard Medical School, Boston, Massachusetts, USA. * Daniel I Chasman, * Lee M Kaplan & * Paul M Ridker * Centre for Genetic Epidemiology and Biostatistics, University of Western Australia, Crawley, Western Australia, Australia. * Matthew N Cooper, * Robert W Lawrence, * Jennie Hui & * Lyle J Palmer * Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. * John-Olov Jansson * University Vita-Salute San Raffaele, Division of Nephrology and Dialysis, Milan, Italy. * Maria T S Alibrandi, * Chiara Lanzani & * Paolo Manunta * Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Malmö, Sweden. * Peter Almgren & * Leif C Groop * Department of Biostatistics, University of Washington, Seattle, Washington, USA. * Alice M Arnold & * Barbara McKnight * Collaborative Health Studies Coordinating Center, Seattle, Washington, USA. * Alice M Arnold * INSERM Centre de recherche en Epidémiologie et Santé des Populations (CESP) Centre for Research in Epidemiology and Public Health U1018, Villejuif, France. * Beverley Balkau * University Paris Sud 11, Unité Mixte de Recherche en Santé (UMRS) 1018, Villejuif, France. * Beverley Balkau * Multidisciplinary Cardiovascular Research Centre (MCRC), Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds, UK. * Anthony J Balmforth & * Alistair S Hall * Department of Social Medicine, University of Bristol, Bristol, UK. * Yoav Ben-Shlomo * Institute of Experimental Paediatric Endocrinology, Charité Universitätsmedizin Berlin, Berlin, Germany. * Heike Biebermann, * Susanna Wiegand & * Heiko Krude * Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK. * Alexandra I F Blakemore & * Philippe Froguel * Department of Medicine III, University of Dresden, Dresden, Germany. * Stefan R Bornstein & * Barbara Ludwig * Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. * Morris J Brown * Division of Endocrinology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. * Thomas A Buchanan * Istituto di Neurogenetica e Neurofarmacologia del Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy. * Fabio Busonero, * Serena Sanna & * Manuela Uda * Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, Scotland, UK. * Harry Campbell, * Sarah H Wild, * Igor Rudan & * James F Wilson * University of Warwick, Warwick Medical School, Coventry, UK. * Francesco P Cappuccio * Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. * Yii-Der Ida Chen & * Talin Haritunians * Clinical Trial Service Unit, Oxford, UK. * Robert Clarke * Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK. * Lachlan Coin, * Paul Elliott, * Ulla Sovio & * Marjo-Riitta Jarvelin * University of Dundee, Ninewells Hospital and Medical School, Dundee, UK. * John Connell * Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Martin den Heijer & * Lambertus A Kiemeney * Department of Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Martin den Heijer * Northshore University Healthsystem, Evanston, Illinois, USA. * Jubao Duan, * Pablo V Gejman & * Alan R Sanders * The London School of Hygiene and Tropical Medicine, London, UK. * Shah Ebrahim * South Asia Network for Chronic Disease, New Dehli, India. * Shah Ebrahim * MRC-Health Protection Agency (HPA) Centre for Environment and Health, London, UK. * Paul Elliott * Cardiovascular Epidemiology and Genetics, Institut Municipal D'investigacio Medica and Centro de Investigación Biomédica en Red CIBER Epidemiología y Salud Pública, Barcelona, Spain. * Roberto Elosua * Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland. * Johan G Eriksson * National Institute for Health and Welfare, Helsinki, Finland. * Johan G Eriksson & * Eero Kajantie * Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland. * Johan G Eriksson * Folkhalsan Research Centre, Helsinki, Finland. * Johan G Eriksson, * Bo Isomaa & * Tiinamaija Tuomi * Vasa Central Hospital, Vasa, Finland. * Johan G Eriksson * Institute of Genetic Medicine, European Academy Bozen-Bolzano (EURAC), Bolzano-Bozen, Italy, Affiliated Institute of the University of Lübeck, Lübeck, Germany. * Maurizio F Facheris, * Andrew A Hicks, * Irene Pichler & * Peter P Pramstaller * Department of Neurology, General Central Hospital, Bolzano, Italy. * Maurizio F Facheris & * Peter P Pramstaller * Department of Internal Medicine B, Ernst-Moritz-Arndt University, Greifswald, Germany. * Stephan B Felix * Pediatric Endocrinology, Diabetes and Obesity Unit, Department of Pediatrics and Adolescent Medicine, Ulm, Germany. * Pamela Fischer-Posovszky & * Martin Wabitsch * Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA. * Aaron R Folsom * Institut für Klinische Chemie und Laboratoriumsmedizin, Universität Greifswald, Greifswald, Germany. * Nele Friedrich, * Sabine Schipf & * Henri Wallaschofski * Center for Neurobehavioral Genetics, University of California, Los Angeles, California, USA. * Nelson B Freimer * Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA. * Mao Fu, * Alan R Shuldiner & * Jeffrey R O'Connell * Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK. * Anuj Goel & * Hugh Watkins * Montreal Heart Institute, Montreal, Quebec, Canada. * Philippe Goyette, * Guillaume Lettre & * Jean-Claude Tardif * Department of Medicine III, Pathobiochemistry, University of Dresden, Dresden, Germany. * Jürgen Gräßler * Merck Research Laboratories, Merck and Co., Inc., Boston, Massachusetts, USA. * Danielle M Greenawalt * Department of Clinical Sciences, Obstetrics and Gynecology, University of Oulu, Oulu, Finland. * Anna-Liisa Hartikainen & * Anneli Pouta * National Institute for Health and Welfare, Department of Chronic Disease Prevention, Chronic Disease Epidemiology and Prevention Unit, Helsinki, Finland. * Aki S Havulinna, * Pekka Jousilahti, * Seppo Koskinen & * Veikko Salomaa * MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland, UK. * Caroline Hayward, * Veronique Vitart & * Alan F Wright * Department of Psychiatry and Midwest Alcoholism Research Center, Washington University School of Medicine, St. Louis, Missouri, USA. * Andrew C Heath * Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, Regensburg, Germany. * Christian Hengstenberg * Regensburg University Medical Center, Innere Medizin II, Regensburg, Germany. * Christian Hengstenberg * Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany. * Anke Hinney, * Susann Scherag, * Carla I G Vogel & * Johannes Hebebrand * Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany. * Georg Homuth * PathWest Laboratory of Western Australia, Department of Molecular Genetics, J Block, QEII Medical Centre, Nedlands, Western Australia, Australia. * Jennie Hui & * John P Beilby * Busselton Population Medical Research Foundation Inc., Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia. * Jennie Hui, * John P Beilby, * Alan L James & * Lyle J Palmer * Division of Research, Kaiser Permanente Northern California, Oakland, California, USA. * Carlos Iribarren * Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA. * Carlos Iribarren * Department of Social Services and Health Care, Jakobstad, Finland. * Bo Isomaa * Core Genotyping Facility, SAIC-Frederick, Inc., National Cancer Institute (NCI)-Frederick, Frederick, Maryland, USA. * Kevin B Jacobs * Institute of Medical Biometry and Epidemiology, University of Marburg, Marburg, Germany. * Ivonne Jarick * Institut für Epidemiologie und Sozialmedizin, Universität Greifswald, Greifswald, Germany. * Ulrich John * Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark. * Torben Jørgensen * Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark. * Torben Jørgensen * National Institute for Health and Welfare, Department of Chronic Disease Prevention, Population Studies Unit, Turku, Finland. * Antti Jula * Institute of Health Sciences, University of Oulu, Oulu, Finland. * Marika Kaakinen & * Marjo-Riitta Jarvelin * Biocenter Oulu, University of Oulu, Oulu, Finland. * Marika Kaakinen & * Marjo-Riitta Jarvelin * Hospital for Children and Adolescents, Helsinki University Central Hospital and University of Helsinki, Hospital District of Helsinki and Uusimaa (HUS), Helsinki, Finland. * Eero Kajantie * Massachusetts General Hospital (MGH) Weight Center, Massachusetts General Hospital, Boston, Massachusetts, USA. * Lee M Kaplan * Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA. * Sekar Kathiresan * Framingham Heart Study of the National, Heart, Lung, and Blood Institute and Boston University, Framingham, Massachusetts, USA. * Sekar Kathiresan & * Christopher J O'Donnell * Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. * Sekar Kathiresan * National Institute for Health and Welfare, Diabetes Prevention Unit, Helsinki, Finland. * Leena Kinnunen, * Jaakko Tuomilehto & * Timo T Valle * Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. * Joshua W Knowles, * Thomas Quertermous & * Themistocles L Assimes * Andrija Stampar School of Public Health, Medical School, University of Zagreb, Zagreb, Croatia. * Ivana Kolcic, * Ozren Polasek & * Lina Zgaga * Interdisciplinary Centre for Clinical Research, University of Leipzig, Leipzig, Germany. * Peter Kovacs * Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, Finland. * Johanna Kuusisto & * Markku Laakso * Nord-Trøndelag Health Study (HUNT) Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway. * Kirsti Kvaløy, * Kristian Midthjell, * Carl G P Platou & * Kristian Hveem * Finnish Institute of Occupational Health, Oulu, Finland. * Jaana Laitinen * Institut inter-regional pour la santé (IRSA), La Riche, France. * Olivier Lantieri * Laboratory of Epidemiology, Demography, Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. * Lenore J Launer & * Tamara B Harris * Department of Clinical Chemistry, University of Tampere and Tampere University Hospital, Tampere, Finland. * Terho Lehtimäki * Department of Medicine, Université de Montréal, Montreal, Quebec, Canada. * Guillaume Lettre & * Jean-Claude Tardif * Human Genetics, Genome Institute of Singapore, Singapore, Singapore. * Jianjun Liu * Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland. * Marja-Liisa Lokki * Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. * Mattias Lorentzon & * Claes Ohlsson * Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK. * Robert N Luben, * Manjinder S Sandhu & * Kay-Tee Khaw * On behalf of the MAGIC (Meta-Analyses of Glucose and Insulin-Related Traits Consortium) investigators. * Department of Endocrinology, Diabetology and Nutrition, Bichat-Claude Bernard University Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France. * Michel Marre * Cardiovascular Genetics Research Unit, Université Henri Poincaré-Nancy 1, Nancy, France. * Michel Marre * Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Queensland, Australia. * Nicholas G Martin * Avon Longitudinal Study of Parents and Children (ALSPAC) Laboratory, Department of Social Medicine, University of Bristol, Bristol, UK. * Wendy L McArdle * Division of Health, Research Board, An Bord Taighde Sláinte, Dublin, Ireland. * Anne McCarthy * Institute of Human Genetics, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany. * Thomas Meitinger * Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. * Thomas Meitinger * Department of Clinical Sciences, Lund University, Malmö, Sweden. * Olle Melander & * Martin Ridderstråle * Molecular Epidemiology Laboratory, Queensland Institute of Medical Research, Queensland, Australia. * Grant W Montgomery * Croatian Centre for Global Health, School of Medicine, University of Split, Split, Croatia. * Rosanda Mulic & * Igor Rudan * Neurogenetics Laboratory, Queensland Institute of Medical Research, Queensland, Australia. * Dale R Nyholt * National Heart, Lung, and Blood Institute, National Institutes of Health, Framingham, Massachusetts, USA. * Christopher J O'Donnell * University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. * Stephen O'Rahilly & * I Sadaf Farooqi * Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands. * Ben Oostra * Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. * Guillaume Paré * Amgen, Cambridge, Massachusetts, USA. * Alex N Parker * Finnish Twin Cohort Study, Department of Public Health, University of Helsinki, Helsinki, Finland. * Kirsi H Pietiläinen & * Jaakko Kaprio * Obesity Research Unit, Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland. * Kirsi H Pietiläinen & * Aila Rissanen * Department of Medicine, Levanger Hospital, The Nord-Trøndelag Health Trust, Levanger, Norway. * Carl G P Platou * Gen-Info Ltd, Zagreb, Croatia. * Ozren Polasek * National Institute for Health and Welfare, Oulu, Finland. * Anneli Pouta & * Marjo-Riitta Jarvelin * Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK. * Suzanne Rafelt & * Nilesh J Samani * Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland. * Olli Raitakari * The Department of Clinical Physiology, Turku University Hospital, Turku, Finland. * Olli Raitakari * Clinical Psychology and Psychotherapy, University of Marburg, Marburg, Germany. * Winfried Rief * Department of Clinical Sciences and Clinical Chemistry, University of Oulu, Oulu, Finland. * Aimo Ruokonen * Ludwig-Maximilians-Universität, Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Munich, Germany. * Peter Rzehak & * H-Erich Wichmann * South Karelia Central Hospital, Lappeenranta, Finland. * Jouko Saramies * Department of Clinical Sciences and Internal Medicine, University of Oulu, Oulu, Finland. * Markku J Savolainen * Institut für Community Medicine, Greifswald, Germany. * Sabine Schipf * Christian-Albrechts-University, University Hospital Schleswig-Holstein, Institute for Clinical Molecular Biology and Department of Internal Medicine I, Kiel, Germany. * Stefan Schreiber * Universität zu Lübeck, Medizinische Klinik II, Lübeck, Germany. * Heribert Schunkert & * Jeanette Erdmann * Division of Cardiology, Cardiovascular Laboratory, Helsinki University Central Hospital, Helsinki, Finland. * Juha Sinisalo & * Markku S Nieminen * Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington, USA. * David S Siscovick * Department of Psychiatry, Instituut voor Extramuraal Geneeskundig Onderzoek (EMGO) Institute, VU University Medical Center, Amsterdam, The Netherlands. * Jan H Smit & * Brenda W Penninx * Department of Haematology, University of Cambridge, Cambridge, UK. * Jonathan Stephens & * Willem H Ouwehand * National Health Service (NHS) Blood and Transplant, Cambridge Centre, Cambridge, UK. * Jonathan Stephens & * Willem H Ouwehand * Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, UK. * John R Thompson & * Nilesh J Samani * Department of Health Sciences, University of Leicester, University Road, Leicester, UK. * John R Thompson * Department of Medicine, University of Leipzig, Leipzig, Germany. * Anke Tönjes & * Michael Stumvoll * Coordination Centre for Clinical Trials, University of Leipzig, Leipzig, Germany. * Anke Tönjes * Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland. * Tiinamaija Tuomi * Research Program of Molecular Medicine, University of Helsinki, Helsinki, Finland. * Tiinamaija Tuomi * Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. * Gert-Jan van Ommen * Center of Medical Systems Biology, Leiden University Medical Center, Leiden, The Netherlands. * Gert-Jan van Ommen * Department of Medicine, University of Turku and Turku University Hospital, Turku, Finland. * Jorma Viikari * INSERM Cardiovascular Genetics team, Centre Investigation Clinique (CIC) 9501, Nancy, France. * Sophie Visvikis-Siest * Steno Diabetes Center, Gentofte, Denmark. * Daniel R Witte * Center for Human Genomics, Wake Forest University, Winston-Salem, North Carolina, USA. * Jianfeng Xu * Department of Physiatrics, Lapland Central Hospital, Rovaniemi, Finland. * Paavo Zitting * School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, Western Australia, Australia. * John P Beilby * Department of Internal Medicine, University of Oulu, Oulu, Finland. * Heikki V Huikuri * School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia. * Alan L James * Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland. * Mika Kähönen * Stanford University School of Medicine, Stanford, California, USA. * Douglas F Levinson * Department of Psychiatry and Human Behavior, University of California, Irvine (UCI), Irvine, California, USA. * Fabio Macciardi * Leipziger Interdisziplinärer Forschungs-komplex zu molekularen Ursachen umwelt- und lebensstilassoziierter Erkrankungen (LIFE) Study Centre, University of Leipzig, Leipzig, Germany. * Michael Stumvoll * Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois (CHUV) University Hospital, Lausanne, Switzerland. * Jacques S Beckmann * Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas, USA. * Eric Boerwinkle * Faculty of Health Science, University of Southern Denmark, Odense, Denmark. * Torben Hansen * New York University Medical Center, New York, New York, USA. * Richard B Hayes * National Institute for Health and Welfare, Department of Mental Health and Substance Abuse Services, Unit for Child and Adolescent Mental Health, Helsinki, Finland. * Jaakko Kaprio * NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK. * Fredrik Karpe & * Mark I McCarthy * Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Lambertus A Kiemeney * Institute of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. * Oluf Pedersen * Faculty of Health Science, University of Aarhus, Aarhus, Denmark. * Oluf Pedersen * Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands. * Brenda W Penninx * Department of Psychiatry, University Medical Centre Groningen, Groningen, The Netherlands. * Brenda W Penninx * Department of Neurology, University of Lübeck, Lübeck, Germany. * Peter P Pramstaller * Institute for Paediatric Nutrition Medicine, Vestische Hospital for Children and Adolescents, University of Witten-Herdecke, Datteln, Germany. * Thomas Reinehr * Department of Medicine III, Prevention and Care of Diabetes, University of Dresden, Dresden, Germany. * Peter E H Schwarz * Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, Maryland, USA. * Alan R Shuldiner * Hjelt Institute, Department of Public Health, University of Helsinki, Helsinki, Finland. * Jaakko Tuomilehto * South Ostrobothnia Central Hospital, Seinajoki, Finland. * Jaakko Tuomilehto * Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois (CHUV) University Hospital, Lausanne, Switzerland. * Gérard Waeber * The Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. * Shaun Purcell & * Leena Peltonen * Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA. * Shaun Purcell * Pacific Biosciences, Menlo Park, California, USA. * Eric E Schadt * Sage Bionetworks, Seattle, Washington, USA. * Eric E Schadt * Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, USA. * Ingrid B Borecki * Division of Intramural Research, National Heart, Lung, and Blood Institute, Framingham Heart Study, Framingham, Massachusetts, USA. * Caroline S Fox * Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, New York, USA. * Robert C Kaplan * Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA. * Karen L Mohlke * Department of Medical Genetics, University of Helsinki, Helsinki, Finland. * Leena Peltonen * Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland, USA. * David Schlessinger * Division of Community Health Sciences, St. George's, University of London, London, UK. * David P Strachan * Klinikum Grosshadern, Munich, Germany. * H-Erich Wichmann * Faculty of Medicine, University of Iceland, Reykjavík, Iceland. * Unnur Thorsteinsdottir & * Kari Stefansson * University of Cambridge Metabolic Research Labs, Institute of Metabolic Science Addenbrooke's Hospital, Cambridge, UK. * Inês Barroso * Carolina Center for Genome Sciences, School of Public Health, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA. * Kari E North * Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. * Joel N Hirschhorn Consortia * MAGIC * on behalf of Procardis Consortium Contributions A full list of author contributions appears in the . Competing financial interests I.B. and spouse own stock in Incyte Ltd and GlaxoSmithKline. J.N.H. is a member of the Scientific Advisory Board, Correlagen, Inc. V.H. has received consultancy fees from GlaxoSmithKline, Lilly and Takeda. A.P. is employed by Amgen. K.S., V.S., G.T., U.T. and G.B.W. are employed by deCODE Genetics. Corresponding authors Correspondence to: * Michael Boehnke (boehnke@umich.edu) or * Kari Stefansson (kstefans@decode.is) or * Kari E North (kari_north@unc.edu) or * Mark I McCarthy (mark.mccarthy@drl.ox.ac.uk) or * Joel N Hirschhorn (joelh@broadinstitute.org) or * Erik Ingelsson (erik.ingelsson@ki.se) or * Ruth J F Loos (ruth.loos@mrc-epid.cam.ac.uk) Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary Text and Figures (6M) Supplementary Tables 1–8, Supplementary Figures 1–4 and Supplementary Note. Additional data
• Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
  - Nat Genet 42(11):949-960 (2010)
  Nature Genetics | Article Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution * Iris M Heid1, 2, 214iris.heid@klinik.uni-regensburg.de Search for this author in: * NPG journals * PubMed * Google Scholar * Anne U Jackson3, 214 Search for this author in: * NPG journals * PubMed * Google Scholar * Joshua C Randall4, 214 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas W Winkler1, 214 Search for this author in: * NPG journals * PubMed * Google Scholar * Lu Qi5, 6, 214 Search for this author in: * NPG journals * PubMed * Google Scholar * Valgerdur Steinthorsdottir7, 214 Search for this author in: * NPG journals * PubMed * Google Scholar * Gudmar Thorleifsson7, 214 Search for this author in: * NPG journals * PubMed * Google Scholar * M Carola Zillikens8, 9 Search for this author in: * NPG journals * PubMed * Google Scholar * Elizabeth K Speliotes10, 11 Search for this author in: * NPG journals * PubMed * Google Scholar * Reedik Mägi4 Search for this author in: * NPG journals * PubMed * Google Scholar * Tsegaselassie Workalemahu5 Search for this author in: * NPG journals * PubMed * Google Scholar * Charles C White12 Search for this author in: * NPG journals * PubMed * Google Scholar * Nabila Bouatia-Naji13, 14 Search for this author in: * NPG journals * PubMed * Google Scholar * Tamara B Harris15 Search for this author in: * NPG journals * PubMed * Google Scholar * Sonja I Berndt16 Search for this author in: * NPG journals * PubMed * Google Scholar * Erik Ingelsson17 Search for this author in: * NPG journals * PubMed * Google Scholar * Cristen J Willer3 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael N Weedon18 Search for this author in: * NPG journals * PubMed * Google Scholar * Jian'an Luan19 Search for this author in: * NPG journals * PubMed * Google Scholar * Sailaja Vedantam10, 20 Search for this author in: * NPG journals * PubMed * Google Scholar * Tõnu Esko21, 22, 23 Search for this author in: * NPG journals * PubMed * Google Scholar * Tuomas O Kilpeläinen19 Search for this author in: * NPG journals * PubMed * Google Scholar * Zoltán Kutalik24, 25 Search for this author in: * NPG journals * PubMed * Google Scholar * Shengxu Li19 Search for this author in: * NPG journals * PubMed * Google Scholar * Keri L Monda26 Search for this author in: * NPG journals * PubMed * Google Scholar * Anna L Dixon27 Search for this author in: * NPG journals * PubMed * Google Scholar * Christopher C Holmes28, 29 Search for this author in: * NPG journals * PubMed * Google Scholar * Lee M Kaplan11, 30, 31 Search for this author in: * NPG journals * PubMed * Google Scholar * Liming Liang32, 33 Search for this author in: * NPG journals * PubMed * Google Scholar * Josine L Min34 Search for this author in: * NPG journals * PubMed * Google Scholar * Miriam F Moffatt35 Search for this author in: * NPG journals * PubMed * Google Scholar * Cliona Molony36 Search for this author in: * NPG journals * PubMed * Google Scholar * George Nicholson29 Search for this author in: * NPG journals * PubMed * Google Scholar * Eric E Schadt37, 38 Search for this author in: * NPG journals * PubMed * Google Scholar * Krina T Zondervan39 Search for this author in: * NPG journals * PubMed * Google Scholar * Mary F Feitosa40 Search for this author in: * NPG journals * PubMed * Google Scholar * Teresa Ferreira4 Search for this author in: * NPG journals * PubMed * Google Scholar * Hana Lango Allen18 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert J Weyant3 Search for this author in: * NPG journals * PubMed * Google Scholar * Eleanor Wheeler41 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew R Wood18 Search for this author in: * NPG journals * PubMed * Google Scholar * MAGIC42 * Karol Estrada8, 9, 43 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael E Goddard44, 45 Search for this author in: * NPG journals * PubMed * Google Scholar * Guillaume Lettre46, 47 Search for this author in: * NPG journals * PubMed * Google Scholar * Massimo Mangino48 Search for this author in: * NPG journals * PubMed * Google Scholar * Dale R Nyholt49 Search for this author in: * NPG journals * PubMed * Google Scholar * Shaun Purcell50, 51, 52 Search for this author in: * NPG journals * PubMed * Google Scholar * Albert Vernon Smith53, 54 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter M Visscher55 Search for this author in: * NPG journals * PubMed * Google Scholar * Jian Yang55 Search for this author in: * NPG journals * PubMed * Google Scholar * Steven A McCarroll50, 56, 57 Search for this author in: * NPG journals * PubMed * Google Scholar * James Nemesh56 Search for this author in: * NPG journals * PubMed * Google Scholar * Benjamin F Voight50, 56, 57 Search for this author in: * NPG journals * PubMed * Google Scholar * Devin Absher58 Search for this author in: * NPG journals * PubMed * Google Scholar * Najaf Amin43 Search for this author in: * NPG journals * PubMed * Google Scholar * Thor Aspelund53, 54 Search for this author in: * NPG journals * PubMed * Google Scholar * Lachlan Coin59 Search for this author in: * NPG journals * PubMed * Google Scholar * Nicole L Glazer60, 61 Search for this author in: * NPG journals * PubMed * Google Scholar * Caroline Hayward62 Search for this author in: * NPG journals * PubMed * Google Scholar * Nancy L Heard-Costa63 Search for this author in: * NPG journals * PubMed * Google Scholar * Jouke-Jan Hottenga64 Search for this author in: * NPG journals * PubMed * Google Scholar * Åsa Johansson65, 66 Search for this author in: * NPG journals * PubMed * Google Scholar * Toby Johnson24, 25, 67, 68 Search for this author in: * NPG journals * PubMed * Google Scholar * Marika Kaakinen69, 70 Search for this author in: * NPG journals * PubMed * Google Scholar * Karen Kapur24, 25 Search for this author in: * NPG journals * PubMed * Google Scholar * Shamika Ketkar40 Search for this author in: * NPG journals * PubMed * Google Scholar * Joshua W Knowles71 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Kraft32, 33 Search for this author in: * NPG journals * PubMed * Google Scholar * Aldi T Kraja40 Search for this author in: * NPG journals * PubMed * Google Scholar * Claudia Lamina2, 72 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael F Leitzmann1 Search for this author in: * NPG journals * PubMed * Google Scholar * Barbara McKnight73 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew P Morris4 Search for this author in: * NPG journals * PubMed * Google Scholar * Ken K Ong19 Search for this author in: * NPG journals * PubMed * Google Scholar * John R B Perry18 Search for this author in: * NPG journals * PubMed * Google Scholar * Marjolein J Peters8, 9 Search for this author in: * NPG journals * PubMed * Google Scholar * Ozren Polasek74, 75 Search for this author in: * NPG journals * PubMed * Google Scholar * Inga Prokopenko4, 76 Search for this author in: * NPG journals * PubMed * Google Scholar * Nigel W Rayner4, 76 Search for this author in: * NPG journals * PubMed * Google Scholar * Samuli Ripatti77, 78 Search for this author in: * NPG journals * PubMed * Google Scholar * Fernando Rivadeneira8, 9, 43 Search for this author in: * NPG journals * PubMed * Google Scholar * Neil R Robertson4, 76 Search for this author in: * NPG journals * PubMed * Google Scholar * Serena Sanna79 Search for this author in: * NPG journals * PubMed * Google Scholar * Ulla Sovio59 Search for this author in: * NPG journals * PubMed * Google Scholar * Ida Surakka77, 78 Search for this author in: * NPG journals * PubMed * Google Scholar * Alexander Teumer80 Search for this author in: * NPG journals * PubMed * Google Scholar * Sophie van Wingerden43 Search for this author in: * NPG journals * PubMed * Google Scholar * Veronique Vitart62 Search for this author in: * NPG journals * PubMed * Google Scholar * Jing Hua Zhao19 Search for this author in: * NPG journals * PubMed * Google Scholar * Christine Cavalcanti-Proença13, 14 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter S Chines81 Search for this author in: * NPG journals * PubMed * Google Scholar * Eva Fisher82 Search for this author in: * NPG journals * PubMed * Google Scholar * Jennifer R Kulzer83 Search for this author in: * NPG journals * PubMed * Google Scholar * Cecile Lecoeur13, 14 Search for this author in: * NPG journals * PubMed * Google Scholar * Narisu Narisu81 Search for this author in: * NPG journals * PubMed * Google Scholar * Camilla Sandholt84 Search for this author in: * NPG journals * PubMed * Google Scholar * Laura J Scott3 Search for this author in: * NPG journals * PubMed * Google Scholar * Kaisa Silander77, 78 Search for this author in: * NPG journals * PubMed * Google Scholar * Klaus Stark85 Search for this author in: * NPG journals * PubMed * Google Scholar * Mari-Liis Tammesoo21 Search for this author in: * NPG journals * PubMed * Google Scholar * Tanya M Teslovich3 Search for this author in: * NPG journals * PubMed * Google Scholar * Nicholas John Timpson86 Search for this author in: * NPG journals * PubMed * Google Scholar * Richard M Watanabe87, 88 Search for this author in: * NPG journals * PubMed * Google Scholar * Ryan Welch3 Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel I Chasman30, 89 Search for this author in: * NPG journals * PubMed * Google Scholar * Matthew N Cooper90 Search for this author in: * NPG journals * PubMed * Google Scholar * John-Olov Jansson91 Search for this author in: * NPG journals * PubMed * Google Scholar * Johannes Kettunen77, 78 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert W Lawrence90 Search for this author in: * NPG journals * PubMed * Google Scholar * Niina Pellikka77, 78 Search for this author in: * NPG journals * PubMed * Google Scholar * Markus Perola77, 78 Search for this author in: * NPG journals * PubMed * Google Scholar * Liesbeth Vandenput92 Search for this author in: * NPG journals * PubMed * Google Scholar * Helene Alavere21 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Almgren93 Search for this author in: * NPG journals * PubMed * Google Scholar * Larry D Atwood63 Search for this author in: * NPG journals * PubMed * Google Scholar * Amanda J Bennett76 Search for this author in: * NPG journals * PubMed * Google Scholar * Reiner Biffar94 Search for this author in: * NPG journals * PubMed * Google Scholar * Lori L Bonnycastle81 Search for this author in: * NPG journals * PubMed * Google Scholar * Stefan R Bornstein95 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas A Buchanan87, 96 Search for this author in: * NPG journals * PubMed * Google Scholar * Harry Campbell97 Search for this author in: * NPG journals * PubMed * Google Scholar * Ian N M Day86 Search for this author in: * NPG journals * PubMed * Google Scholar * Mariano Dei79 Search for this author in: * NPG journals * PubMed * Google Scholar * Marcus Dörr98 Search for this author in: * NPG journals * PubMed * Google Scholar * Paul Elliott59, 99 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael R Erdos81 Search for this author in: * NPG journals * PubMed * Google Scholar * Johan G Eriksson100, 101, 102, 103, 104 Search for this author in: * NPG journals * PubMed * Google Scholar * Nelson B Freimer105 Search for this author in: * NPG journals * PubMed * Google Scholar * Mao Fu106 Search for this author in: * NPG journals * PubMed * Google Scholar * Stefan Gaget13, 14 Search for this author in: * NPG journals * PubMed * Google Scholar * Eco J C Geus64 Search for this author in: * NPG journals * PubMed * Google Scholar * Anette P Gjesing84 Search for this author in: * NPG journals * PubMed * Google Scholar * Harald Grallert2 Search for this author in: * NPG journals * PubMed * Google Scholar * Jürgen Gräßler107 Search for this author in: * NPG journals * PubMed * Google Scholar * Christopher J Groves76 Search for this author in: * NPG journals * PubMed * Google Scholar * Candace Guiducci10 Search for this author in: * NPG journals * PubMed * Google Scholar * Anna-Liisa Hartikainen108 Search for this author in: * NPG journals * PubMed * Google Scholar * Neelam Hassanali76 Search for this author in: * NPG journals * PubMed * Google Scholar * Aki S Havulinna109 Search for this author in: * NPG journals * PubMed * Google Scholar * Karl-Heinz Herzig70, 110, 111 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew A Hicks112 Search for this author in: * NPG journals * PubMed * Google Scholar * Jennie Hui90, 113, 114 Search for this author in: * NPG journals * PubMed * Google Scholar * Wilmar Igl65 Search for this author in: * NPG journals * PubMed * Google Scholar * Pekka Jousilahti109 Search for this author in: * NPG journals * PubMed * Google Scholar * Antti Jula115 Search for this author in: * NPG journals * PubMed * Google Scholar * Eero Kajantie101, 116 Search for this author in: * NPG journals * PubMed * Google Scholar * Leena Kinnunen117 Search for this author in: * NPG journals * PubMed * Google Scholar * Ivana Kolcic74 Search for this author in: * NPG journals * PubMed * Google Scholar * Seppo Koskinen109 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Kovacs118 Search for this author in: * NPG journals * PubMed * Google Scholar * Heyo K Kroemer119 Search for this author in: * NPG journals * PubMed * Google Scholar * Vjekoslav Krzelj120 Search for this author in: * NPG journals * PubMed * Google Scholar * Johanna Kuusisto121 Search for this author in: * NPG journals * PubMed * Google Scholar * Kirsti Kvaloy122 Search for this author in: * NPG journals * PubMed * Google Scholar * Jaana Laitinen123 Search for this author in: * NPG journals * PubMed * Google Scholar * Olivier Lantieri124 Search for this author in: * NPG journals * PubMed * Google Scholar * G Mark Lathrop125 Search for this author in: * NPG journals * PubMed * Google Scholar * Marja-Liisa Lokki126 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert N Luben127 Search for this author in: * NPG journals * PubMed * Google Scholar * Barbara Ludwig95 Search for this author in: * NPG journals * PubMed * Google Scholar * Wendy L McArdle128 Search for this author in: * NPG journals * PubMed * Google Scholar * Anne McCarthy129 Search for this author in: * NPG journals * PubMed * Google Scholar * Mario A Morken81 Search for this author in: * NPG journals * PubMed * Google Scholar * Mari Nelis21, 22, 23 Search for this author in: * NPG journals * PubMed * Google Scholar * Matt J Neville76 Search for this author in: * NPG journals * PubMed * Google Scholar * Guillaume Paré130 Search for this author in: * NPG journals * PubMed * Google Scholar * Alex N Parker131 Search for this author in: * NPG journals * PubMed * Google Scholar * John F Peden4, 132 Search for this author in: * NPG journals * PubMed * Google Scholar * Irene Pichler112 Search for this author in: * NPG journals * PubMed * Google Scholar * Kirsi H Pietiläinen133, 134 Search for this author in: * NPG journals * PubMed * Google Scholar * Carl G P Platou122, 135 Search for this author in: * NPG journals * PubMed * Google Scholar * Anneli Pouta108, 136 Search for this author in: * NPG journals * PubMed * Google Scholar * Martin Ridderstråle137 Search for this author in: * NPG journals * PubMed * Google Scholar * Nilesh J Samani138, 139 Search for this author in: * NPG journals * PubMed * Google Scholar * Jouko Saramies140 Search for this author in: * NPG journals * PubMed * Google Scholar * Juha Sinisalo141 Search for this author in: * NPG journals * PubMed * Google Scholar * Jan H Smit142 Search for this author in: * NPG journals * PubMed * Google Scholar * Rona J Strawbridge143 Search for this author in: * NPG journals * PubMed * Google Scholar * Heather M Stringham3 Search for this author in: * NPG journals * PubMed * Google Scholar * Amy J Swift81 Search for this author in: * NPG journals * PubMed * Google Scholar * Maris Teder-Laving22, 23 Search for this author in: * NPG journals * PubMed * Google Scholar * Brian Thomson10 Search for this author in: * NPG journals * PubMed * Google Scholar * Gianluca Usala79 Search for this author in: * NPG journals * PubMed * Google Scholar * Joyce B J van Meurs8, 9, 43 Search for this author in: * NPG journals * PubMed * Google Scholar * Gert-Jan van Ommen144, 145 Search for this author in: * NPG journals * PubMed * Google Scholar * Vincent Vatin13, 14 Search for this author in: * NPG journals * PubMed * Google Scholar * Claudia B Volpato112 Search for this author in: * NPG journals * PubMed * Google Scholar * Henri Wallaschofski146 Search for this author in: * NPG journals * PubMed * Google Scholar * G Bragi Walters7 Search for this author in: * NPG journals * PubMed * Google Scholar * Elisabeth Widen77 Search for this author in: * NPG journals * PubMed * Google Scholar * Sarah H Wild97 Search for this author in: * NPG journals * PubMed * Google Scholar * Gonneke Willemsen64 Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel R Witte147 Search for this author in: * NPG journals * PubMed * Google Scholar * Lina Zgaga74 Search for this author in: * NPG journals * PubMed * Google Scholar * Paavo Zitting148 Search for this author in: * NPG journals * PubMed * Google Scholar * John P Beilby113, 114, 149 Search for this author in: * NPG journals * PubMed * Google Scholar * Alan L James114, 150 Search for this author in: * NPG journals * PubMed * Google Scholar * Mika Kähönen151 Search for this author in: * NPG journals * PubMed * Google Scholar * Terho Lehtimäki152 Search for this author in: * NPG journals * PubMed * Google Scholar * Markku S Nieminen141 Search for this author in: * NPG journals * PubMed * Google Scholar * Claes Ohlsson92 Search for this author in: * NPG journals * PubMed * Google Scholar * Lyle J Palmer90, 114 Search for this author in: * NPG journals * PubMed * Google Scholar * Olli Raitakari153, 154 Search for this author in: * NPG journals * PubMed * Google Scholar * Paul M Ridker30, 89 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Stumvoll155, 156 Search for this author in: * NPG journals * PubMed * Google Scholar * Anke Tönjes155, 157 Search for this author in: * NPG journals * PubMed * Google Scholar * Jorma Viikari158 Search for this author in: * NPG journals * PubMed * Google Scholar * Beverley Balkau159, 160 Search for this author in: * NPG journals * PubMed * Google Scholar * Yoav Ben-Shlomo161 Search for this author in: * NPG journals * PubMed * Google Scholar * Richard N Bergman87 Search for this author in: * NPG journals * PubMed * Google Scholar * Heiner Boeing82 Search for this author in: * NPG journals * PubMed * Google Scholar * George Davey Smith86 Search for this author in: * NPG journals * PubMed * Google Scholar * Shah Ebrahim162, 163 Search for this author in: * NPG journals * PubMed * Google Scholar * Philippe Froguel13, 14, 164 Search for this author in: * NPG journals * PubMed * Google Scholar * Torben Hansen84, 165 Search for this author in: * NPG journals * PubMed * Google Scholar * Christian Hengstenberg166, 167 Search for this author in: * NPG journals * PubMed * Google Scholar * Kristian Hveem122 Search for this author in: * NPG journals * PubMed * Google Scholar * Bo Isomaa103, 168 Search for this author in: * NPG journals * PubMed * Google Scholar * Torben Jørgensen169, 170 Search for this author in: * NPG journals * PubMed * Google Scholar * Fredrik Karpe76, 171 Search for this author in: * NPG journals * PubMed * Google Scholar * Kay-Tee Khaw127 Search for this author in: * NPG journals * PubMed * Google Scholar * Markku Laakso121 Search for this author in: * NPG journals * PubMed * Google Scholar * Debbie A Lawlor86 Search for this author in: * NPG journals * PubMed * Google Scholar * Michel Marre172, 173 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas Meitinger174, 175 Search for this author in: * NPG journals * PubMed * Google Scholar * Andres Metspalu21, 22, 23 Search for this author in: * NPG journals * PubMed * Google Scholar * Kristian Midthjell122 Search for this author in: * NPG journals * PubMed * Google Scholar * Oluf Pedersen84, 176, 177 Search for this author in: * NPG journals * PubMed * Google Scholar * Veikko Salomaa109 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter E H Schwarz178 Search for this author in: * NPG journals * PubMed * Google Scholar * Tiinamaija Tuomi103, 179, 180 Search for this author in: * NPG journals * PubMed * Google Scholar * Jaakko Tuomilehto117, 181, 182 Search for this author in: * NPG journals * PubMed * Google Scholar * Timo T Valle117 Search for this author in: * NPG journals * PubMed * Google Scholar * Nicholas J Wareham19 Search for this author in: * NPG journals * PubMed * Google Scholar * Alice M Arnold73, 183 Search for this author in: * NPG journals * PubMed * Google Scholar * Jacques S Beckmann24, 184 Search for this author in: * NPG journals * PubMed * Google Scholar * Sven Bergmann24, 25 Search for this author in: * NPG journals * PubMed * Google Scholar * Eric Boerwinkle185 Search for this author in: * NPG journals * PubMed * Google Scholar * Dorret I Boomsma64 Search for this author in: * NPG journals * PubMed * Google Scholar * Mark J Caulfield68 Search for this author in: * NPG journals * PubMed * Google Scholar * Francis S Collins81 Search for this author in: * NPG journals * PubMed * Google Scholar * Gudny Eiriksdottir53 Search for this author in: * NPG journals * PubMed * Google Scholar * Vilmundur Gudnason53, 54 Search for this author in: * NPG journals * PubMed * Google Scholar * Ulf Gyllensten65 Search for this author in: * NPG journals * PubMed * Google Scholar * Anders Hamsten143 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew T Hattersley18 Search for this author in: * NPG journals * PubMed * Google Scholar * Albert Hofman9, 43 Search for this author in: * NPG journals * PubMed * Google Scholar * Frank B Hu5, 6, 32 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas Illig2 Search for this author in: * NPG journals * PubMed * Google Scholar * Carlos Iribarren186, 187 Search for this author in: * NPG journals * PubMed * Google Scholar * Marjo-Riitta Jarvelin59, 69, 70, 136 Search for this author in: * NPG journals * PubMed * Google Scholar * W H Linda Kao188 Search for this author in: * NPG journals * PubMed * Google Scholar * Jaakko Kaprio77, 133, 189 Search for this author in: * NPG journals * PubMed * Google Scholar * Lenore J Launer15 Search for this author in: * NPG journals * PubMed * Google Scholar * Patricia B Munroe68 Search for this author in: * NPG journals * PubMed * Google Scholar * Ben Oostra190 Search for this author in: * NPG journals * PubMed * Google Scholar * Brenda W Penninx142, 191, 192 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter P Pramstaller112, 193, 194 Search for this author in: * NPG journals * PubMed * Google Scholar * Bruce M Psaty195, 196 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas Quertermous71 Search for this author in: * NPG journals * PubMed * Google Scholar * Aila Rissanen134 Search for this author in: * NPG journals * PubMed * Google Scholar * Igor Rudan97, 120 Search for this author in: * NPG journals * PubMed * Google Scholar * Alan R Shuldiner106, 197 Search for this author in: * NPG journals * PubMed * Google Scholar * Nicole Soranzo41, 48 Search for this author in: * NPG journals * PubMed * Google Scholar * Timothy D Spector48 Search for this author in: * NPG journals * PubMed * Google Scholar * Ann-Christine Syvanen198 Search for this author in: * NPG journals * PubMed * Google Scholar * Manuela Uda79 Search for this author in: * NPG journals * PubMed * Google Scholar * André Uitterlinden8, 9, 43 Search for this author in: * NPG journals * PubMed * Google Scholar * Henry Völzke199 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Vollenweider200 Search for this author in: * NPG journals * PubMed * Google Scholar * James F Wilson97 Search for this author in: * NPG journals * PubMed * Google Scholar * Jacqueline C Witteman9, 43 Search for this author in: * NPG journals * PubMed * Google Scholar * Alan F Wright62 Search for this author in: * NPG journals * PubMed * Google Scholar * Gonçalo R Abecasis3 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Boehnke3 Search for this author in: * NPG journals * PubMed * Google Scholar * Ingrid B Borecki40, 201 Search for this author in: * NPG journals * PubMed * Google Scholar * Panos Deloukas41 Search for this author in: * NPG journals * PubMed * Google Scholar * Timothy M Frayling18 Search for this author in: * NPG journals * PubMed * Google Scholar * Leif C Groop93 Search for this author in: * NPG journals * PubMed * Google Scholar * Talin Haritunians202 Search for this author in: * NPG journals * PubMed * Google Scholar * David J Hunter5, 6, 32 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert C Kaplan203 Search for this author in: * NPG journals * PubMed * Google Scholar * Kari E North26, 204 Search for this author in: * NPG journals * PubMed * Google Scholar * Jeffrey R O'Connell106 Search for this author in: * NPG journals * PubMed * Google Scholar * Leena Peltonen41, 51, 77, 101, 205 Search for this author in: * NPG journals * PubMed * Google Scholar * David Schlessinger206 Search for this author in: * NPG journals * PubMed * Google Scholar * David P Strachan207 Search for this author in: * NPG journals * PubMed * Google Scholar * Joel N Hirschhorn10, 20, 208 Search for this author in: * NPG journals * PubMed * Google Scholar * Themistocles L Assimes71 Search for this author in: * NPG journals * PubMed * Google Scholar * H-Erich Wichmann2, 209, 210 Search for this author in: * NPG journals * PubMed * Google Scholar * Unnur Thorsteinsdottir7, 211 Search for this author in: * NPG journals * PubMed * Google Scholar * Cornelia M van Duijn9, 43 Search for this author in: * NPG journals * PubMed * Google Scholar * Kari Stefansson7, 211, 215 Search for this author in: * NPG journals * PubMed * Google Scholar * L Adrienne Cupples12, 215 Search for this author in: * NPG journals * PubMed * Google Scholar * Ruth J F Loos19, 215 Search for this author in: * NPG journals * PubMed * Google Scholar * Inês Barroso41, 212, 215 Search for this author in: * NPG journals * PubMed * Google Scholar * Mark I McCarthy4, 76, 171, 215mark.mccarthy@drl.ox.ac.uk Search for this author in: * NPG journals * PubMed * Google Scholar * Caroline S Fox213, 215foxca@nhlbi.nih.gov Search for this author in: * NPG journals * PubMed * Google Scholar * Karen L Mohlke83, 215mohlke@med.unc.edu Search for this author in: * NPG journals * PubMed * Google Scholar * Cecilia M Lindgren4, 76, 215celi@well.ox.ac.uk Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 42 ,Pages:949–960Year published:(2010)DOI:doi:10.1038/ng.685Received06 May 2010Accepted15 September 2010Published online10 October 2010 Abstract * Abstract * Author information * Supplementary information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10−9 to P = 1.8 × 10−40) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10−3 to P = 1.2 × 10−13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and revea! l strong gene-by-sex interactions. View full text Figures at a glance * Figure 1: Genome-wide association analyses for WHR in discovery studies. () Manhattan plot shows results of the WHR association meta-analysis in discovery studies (with P values on the y axis and the SNP genomic position on the x axis). Colored genomic loci indicate significant association (P < 5 × 10−8) detected previously (blue)13, in our GWAS stage (red) and after the meta-analysis combining GWAS data with that from the follow-up studies (orange). Two loci tested in the follow-up stage did not achieve genome-wide significance (green). () Quantile-quantile plot of SNPs for the discovery meta-analysis of WHR (black) and after removing SNPs within 1 Mb of either the recently reported LYPLAL1 signal (blue) or the 14 significant associations (green). The gray area represents the 95% CI around the test statistic under the null distribution. * Figure 2: Regional plots of 14 loci with genome-wide significant association. Shown is the SNP association with WHR in the meta-analysis of discovery studies for 14 loci (with –log10P values on the y axis and the SNP genomic position on the x axis). In each panel, an index SNP is denoted with a purple diamond and plotted using the P attained across discovery and follow-up data (Table 1). Estimated recombination rates are plotted in blue. SNPs are colored to reflect LD with the index SNP (pairwise r2 values from HapMap CEU). Gene and microRNA annotations are from the UCSC genome browser. * Figure 3: Association of the 14 WHR loci with waist and hip circumference. β coefficients for waist circumference (WC, x axis) and hip circumference (HIP, y axis) in women and men derived from the joint discovery and follow-up analysis. P for WC and HIP are represented by color. In men, gray gene labels refer to those SNPs that were not significant in the male-specific WHR analysis. More details can be found in Supplementary Table 3. Author information * Abstract * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Iris M Heid, * Anne U Jackson, * Joshua C Randall, * Thomas W Winkler, * Lu Qi, * Valgerdur Steinthorsdottir & * Gudmar Thorleifsson Affiliations * Regensburg University Medical Center, Department of Epidemiology and Preventive Medicine, Regensburg, Germany. * Iris M Heid, * Thomas W Winkler & * Michael F Leitzmann * Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. * Iris M Heid, * Claudia Lamina, * Harald Grallert, * Thomas Illig & * H-Erich Wichmann * Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA. * Anne U Jackson, * Cristen J Willer, * Robert J Weyant, * Laura J Scott, * Tanya M Teslovich, * Ryan Welch, * Heather M Stringham, * Gonçalo R Abecasis & * Michael Boehnke * Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. * Joshua C Randall, * Reedik Mägi, * Teresa Ferreira, * Andrew P Morris, * Inga Prokopenko, * Nigel W Rayner, * Neil R Robertson, * John F Peden, * Mark I McCarthy & * Cecilia M Lindgren * Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA. * Lu Qi, * Tsegaselassie Workalemahu, * Frank B Hu & * David J Hunter * Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. * Lu Qi, * Frank B Hu & * David J Hunter * deCODE Genetics, Reykjavik, Iceland. * Valgerdur Steinthorsdottir, * Gudmar Thorleifsson, * G Bragi Walters, * Unnur Thorsteinsdottir & * Kari Stefansson * Department of Internal Medicine, Erasmus Medical Center (MC), Rotterdam, The Netherlands. * M Carola Zillikens, * Karol Estrada, * Marjolein J Peters, * Fernando Rivadeneira, * Joyce B J van Meurs & * André Uitterlinden * Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, The Netherlands. * M Carola Zillikens, * Karol Estrada, * Marjolein J Peters, * Fernando Rivadeneira, * Joyce B J van Meurs, * Albert Hofman, * André Uitterlinden, * Jacqueline C Witteman & * Cornelia M van Duijn * Metabolism Initiative and Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. * Elizabeth K Speliotes, * Sailaja Vedantam, * Candace Guiducci, * Brian Thomson & * Joel N Hirschhorn * Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA. * Elizabeth K Speliotes & * Lee M Kaplan * Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA. * Charles C White & * L Adrienne Cupples * Centre National de la Recherche Scientifique (CNRS), UMR8199-IBL-Institut Pasteur de Lille, Lille, France. * Nabila Bouatia-Naji, * Christine Cavalcanti-Proença, * Cecile Lecoeur, * Stefan Gaget, * Vincent Vatin & * Philippe Froguel * University Lille Nord de France, Lille, France. * Nabila Bouatia-Naji, * Christine Cavalcanti-Proença, * Cecile Lecoeur, * Stefan Gaget, * Vincent Vatin & * Philippe Froguel * Laboratory of Epidemiology, Demography, Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. * Tamara B Harris & * Lenore J Launer * Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA. * Sonja I Berndt * Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. * Erik Ingelsson * Genetics of Complex Traits, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK. * Michael N Weedon, * Hana Lango Allen, * Andrew R Wood, * John R B Perry, * Andrew T Hattersley & * Timothy M Frayling * Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. * Jian'an Luan, * Tuomas O Kilpeläinen, * Shengxu Li, * Ken K Ong, * Jing Hua Zhao, * Nicholas J Wareham & * Ruth J F Loos * Divisions of Genetics and Endocrinology and Program in Genomics, Children's Hospital, Boston, Massachusetts, USA. * Sailaja Vedantam & * Joel N Hirschhorn * Estonian Genome Center, University of Tartu, Tartu, Estonia. * Tõnu Esko, * Mari-Liis Tammesoo, * Helene Alavere, * Mari Nelis & * Andres Metspalu * Estonian Biocenter, Tartu, Estonia. * Tõnu Esko, * Mari Nelis, * Maris Teder-Laving & * Andres Metspalu * Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. * Tõnu Esko, * Mari Nelis, * Maris Teder-Laving & * Andres Metspalu * Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland. * Zoltán Kutalik, * Toby Johnson, * Karen Kapur, * Jacques S Beckmann & * Sven Bergmann * Swiss Institute of Bioinformatics, Lausanne, Switzerland. * Zoltán Kutalik, * Toby Johnson, * Karen Kapur & * Sven Bergmann * Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. * Keri L Monda & * Kari E North * Department of Pharmacy and Pharmacology, University of Bath, Bath, UK. * Anna L Dixon * MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire, UK. * Christopher C Holmes * Department of Statistics, University of Oxford, Oxford, UK. * Christopher C Holmes & * George Nicholson * Harvard Medical School, Boston, Massachusetts, USA. * Lee M Kaplan, * Daniel I Chasman & * Paul M Ridker * Massachusetts General Hospital (MGH) Weight Center, Massachusetts General Hospital, Boston, Massachusetts, USA. * Lee M Kaplan * Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. * Liming Liang, * Peter Kraft, * Frank B Hu & * David J Hunter * Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA. * Liming Liang & * Peter Kraft * Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. * Josine L Min * National Heart and Lung Institute, Imperial College London, London, UK. * Miriam F Moffatt * Merck Research Laboratories, Merck & Co., Inc., Boston, Massachusetts, USA. * Cliona Molony * Pacific Biosciences, Menlo Park, California, USA. * Eric E Schadt * Sage Bionetworks, Seattle, Washington, USA. * Eric E Schadt * Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, Oxford, UK. * Krina T Zondervan * Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA. * Mary F Feitosa, * Shamika Ketkar, * Aldi T Kraja & * Ingrid B Borecki * Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. * Eleanor Wheeler, * Nicole Soranzo, * Panos Deloukas, * Leena Peltonen & * Inês Barroso * On behalf of the MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium) investigators. * Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. * Karol Estrada, * Najaf Amin, * Fernando Rivadeneira, * Sophie van Wingerden, * Joyce B J van Meurs, * Albert Hofman, * André Uitterlinden, * Jacqueline C Witteman & * Cornelia M van Duijn * University of Melbourne, Parkville, Australia. * Michael E Goddard * Department of Primary Industries, Melbourne, Victoria, Australia. * Michael E Goddard * Montreal Heart Institute, Montreal, Quebec, Canada. * Guillaume Lettre * Department of Medicine, Université de Montréal, Montreal, Quebec, Canada. * Guillaume Lettre * Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. * Massimo Mangino, * Nicole Soranzo & * Timothy D Spector * Neurogenetics Laboratory, Queensland Institute of Medical Research, Queensland, Australia. * Dale R Nyholt * Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. * Shaun Purcell, * Steven A McCarroll & * Benjamin F Voight * The Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. * Shaun Purcell & * Leena Peltonen * Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA. * Shaun Purcell * Icelandic Heart Association, Kopavogur, Iceland. * Albert Vernon Smith, * Thor Aspelund, * Gudny Eiriksdottir & * Vilmundur Gudnason * University of Iceland, Reykjavik, Iceland. * Albert Vernon Smith, * Thor Aspelund & * Vilmundur Gudnason * Queensland Statistical Genetics Laboratory, Queensland Institute of Medical Research, Queensland, Australia. * Peter M Visscher & * Jian Yang * Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. * Steven A McCarroll, * James Nemesh & * Benjamin F Voight * Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA. * Steven A McCarroll & * Benjamin F Voight * Hudson Alpha Institute for Biotechnology, Huntsville, Alabama, USA. * Devin Absher * Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK. * Lachlan Coin, * Ulla Sovio, * Paul Elliott & * Marjo-Riitta Jarvelin * Department of Medicine, University of Washington, Seattle, Washington, USA. * Nicole L Glazer * Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA. * Nicole L Glazer * MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland, UK. * Caroline Hayward, * Veronique Vitart & * Alan F Wright * Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA. * Nancy L Heard-Costa & * Larry D Atwood * Department of Biological Psychology, Vrije Universiteit (VU) University Amsterdam, Amsterdam, The Netherlands. * Jouke-Jan Hottenga, * Eco J C Geus, * Gonneke Willemsen & * Dorret I Boomsma * Department of Genetics and Pathology, Rudbeck Laboratory, University of Uppsala, Uppsala, Sweden. * Åsa Johansson, * Wilmar Igl & * Ulf Gyllensten * Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway. * Åsa Johansson * Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK. * Toby Johnson * Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London UK. * Toby Johnson, * Mark J Caulfield & * Patricia B Munroe * Institute of Health Sciences, University of Oulu, Oulu, Finland. * Marika Kaakinen & * Marjo-Riitta Jarvelin * Biocenter Oulu, University of Oulu, Oulu, Finland. * Marika Kaakinen, * Karl-Heinz Herzig & * Marjo-Riitta Jarvelin * Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. * Joshua W Knowles, * Thomas Quertermous & * Themistocles L Assimes * Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria. * Claudia Lamina * Department of Biostatistics, University of Washington, Seattle, Washington, USA. * Barbara McKnight & * Alice M Arnold * Andrija Stampar School of Public Health, Medical School, University of Zagreb, Zagreb, Croatia. * Ozren Polasek, * Ivana Kolcic & * Lina Zgaga * Gen-Info Ltd, Zagreb, Croatia. * Ozren Polasek * Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK. * Inga Prokopenko, * Nigel W Rayner, * Neil R Robertson, * Amanda J Bennett, * Christopher J Groves, * Neelam Hassanali, * Matt J Neville, * Fredrik Karpe, * Mark I McCarthy & * Cecilia M Lindgren * Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. * Samuli Ripatti, * Ida Surakka, * Kaisa Silander, * Johannes Kettunen, * Niina Pellikka, * Markus Perola, * Elisabeth Widen, * Jaakko Kaprio & * Leena Peltonen * National Institute for Health and Welfare, Department of Chronic Disease Prevention, Unit of Public Health Genomics, Helsinki, Finland. * Samuli Ripatti, * Ida Surakka, * Kaisa Silander, * Johannes Kettunen, * Niina Pellikka & * Markus Perola * Istituto di Neurogenetica e Neurofarmacologia del CNR, Monserrato, Cagliari, Italy. * Serena Sanna, * Mariano Dei, * Gianluca Usala & * Manuela Uda * Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany. * Alexander Teumer * National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. * Peter S Chines, * Narisu Narisu, * Lori L Bonnycastle, * Michael R Erdos, * Mario A Morken, * Amy J Swift & * Francis S Collins * Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. * Eva Fisher & * Heiner Boeing * Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA. * Jennifer R Kulzer & * Karen L Mohlke * Hagedorn Research Institute, Gentofte, Denmark. * Camilla Sandholt, * Anette P Gjesing, * Torben Hansen & * Oluf Pedersen * Regensburg University Medical Center, Clinic and Policlinic for Internal Medicine II, Regensburg, Germany. * Klaus Stark * MRC Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, Oakfield House, Bristol, UK. * Nicholas John Timpson, * Ian N M Day, * George Davey Smith & * Debbie A Lawlor * Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. * Richard M Watanabe, * Thomas A Buchanan & * Richard N Bergman * Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. * Richard M Watanabe * Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. * Daniel I Chasman & * Paul M Ridker * Centre for Genetic Epidemiology and Biostatistics, University of Western Australia, Crawley, Western Australia, Australia. * Matthew N Cooper, * Robert W Lawrence, * Jennie Hui & * Lyle J Palmer * Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. * John-Olov Jansson * Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. * Liesbeth Vandenput & * Claes Ohlsson * Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Malmö, Sweden. * Peter Almgren & * Leif C Groop * Zentrum für Zahn-, Mund- und Kieferheilkunde, Greifswald, Germany. * Reiner Biffar * Department of Medicine III, University of Dresden, Dresden, Germany. * Stefan R Bornstein & * Barbara Ludwig * Division of Endocrinology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. * Thomas A Buchanan * Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, Scotland, UK. * Harry Campbell, * Sarah H Wild, * Igor Rudan & * James F Wilson * Department of Internal Medicine B, Ernst-Moritz-Arndt University, Greifswald, Germany. * Marcus Dörr * MRC-Health Protection Agency (HPA) Centre for Environment and Health, London, UK. * Paul Elliott * Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland. * Johan G Eriksson * National Institute for Health and Welfare, Helsinki, Finland. * Johan G Eriksson, * Eero Kajantie & * Leena Peltonen * Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland. * Johan G Eriksson * Folkhalsan Research Centre, Helsinki, Finland. * Johan G Eriksson, * Bo Isomaa & * Tiinamaija Tuomi * Vasa Central Hospital, Vasa, Finland. * Johan G Eriksson * Center for Neurobehavioral Genetics, University of California, Los Angeles, California, USA. * Nelson B Freimer * Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA. * Mao Fu, * Alan R Shuldiner & * Jeffrey R O'Connell * Department of Medicine III, Pathobiochemistry, University of Dresden, Dresden, Germany. * Jürgen Gräßler * Department of Clinical Sciences/Obstetrics and Gynecology, University of Oulu, Oulu, Finland. * Anna-Liisa Hartikainen & * Anneli Pouta * National Institute for Health and Welfare, Department of Chronic Disease Prevention, Chronic Disease Epidemiology and Prevention Unit, Helsinki, Finland. * Aki S Havulinna, * Pekka Jousilahti, * Seppo Koskinen & * Veikko Salomaa * Institute of Biomedicine, Department of Physiology, University of Oulu, Oulu, Finland. * Karl-Heinz Herzig * Department of Psychiatry, Kuopio University Hospital and University of Kuopio, Kuopio, Finland. * Karl-Heinz Herzig * Institute of Genetic Medicine, European Academy Bozen-Bolzano (EURAC), Bolzano-Bozen, Italy (affiliated Institute of the University of Lübeck, Lübeck, Germany). * Andrew A Hicks, * Irene Pichler, * Claudia B Volpato & * Peter P Pramstaller * PathWest Laboratory of Western Australia, Department of Molecular Genetics, J Block, QEII Medical Centre, Nedlands, Western Australia, Australia. * Jennie Hui & * John P Beilby * Busselton Population Medical Research Foundation Inc., Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia. * Jennie Hui, * John P Beilby, * Alan L James & * Lyle J Palmer * National Institute for Health and Welfare, Department of Chronic Disease Prevention, Population Studies Unit, Turku, Finland. * Antti Jula * Hospital for Children and Adolescents, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland. * Eero Kajantie * National Institute for Health and Welfare, Diabetes Prevention Unit, Helsinki, Finland. * Leena Kinnunen, * Jaakko Tuomilehto & * Timo T Valle * Interdisciplinary Centre for Clinical Research, University of Leipzig, Leipzig, Germany. * Peter Kovacs * Institut für Pharmakologie, Universität Greifswald, Greifswald, Germany. * Heyo K Kroemer * Croatian Centre for Global Health, School of Medicine, University of Split, Split, Croatia. * Vjekoslav Krzelj & * Igor Rudan * Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, Finland. * Johanna Kuusisto & * Markku Laakso * Nord-Trøndelag Health Study (HUNT) Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway. * Kirsti Kvaloy, * Carl G P Platou, * Kristian Hveem & * Kristian Midthjell * Finnish Institute of Occupational Health, Oulu, Finland. * Jaana Laitinen * Institut inter-regional pour la sante (IRSA), La Riche, France. * Olivier Lantieri * Centre National de Genotypage, Evry, Paris, France. * G Mark Lathrop * Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland. * Marja-Liisa Lokki * Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK. * Robert N Luben & * Kay-Tee Khaw * Avon Longitudinal Study of Parents and Children (ALSPAC) Laboratory, Department of Social Medicine, University of Bristol, Bristol, UK. * Wendy L McArdle * Division of Health, Research Board, An Bord Taighde Sláinte, Dublin, Ireland. * Anne McCarthy * Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. * Guillaume Paré * Amgen, Cambridge, Massachusetts, USA. * Alex N Parker * Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK. * John F Peden * Finnish Twin Cohort Study, Department of Public Health, University of Helsinki, Helsinki, Finland. * Kirsi H Pietiläinen & * Jaakko Kaprio * Obesity Research Unit, Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland. * Kirsi H Pietiläinen & * Aila Rissanen * Department of Medicine, Levanger Hospital, The Nord-Trøndelag Health Trust, Levanger, Norway. * Carl G P Platou * National Institute for Health and Welfare, Oulu, Finland. * Anneli Pouta & * Marjo-Riitta Jarvelin * Department of Clinical Sciences, Lund University, Malmö, Sweden. * Martin Ridderstråle * Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK. * Nilesh J Samani * Leicester National Institute for Health Research (NIHR) Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, UK. * Nilesh J Samani * South Karelia Central Hospital, Lappeenranta, Finland. * Jouko Saramies * Division of Cardiology, Cardiovascular Laboratory, Helsinki University Central Hospital, Helsinki, Finland. * Juha Sinisalo & * Markku S Nieminen * Department of Psychiatry/Instituut voor Extramuraal Geneeskundig Onderzoek (EMGO) Institute, VU University Medical Center, Amsterdam, The Netherlands. * Jan H Smit & * Brenda W Penninx * Atherosclerosis Research Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. * Rona J Strawbridge & * Anders Hamsten * Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. * Gert-Jan van Ommen * Center of Medical Systems Biology, Leiden University Medical Center, Leiden, The Netherlands. * Gert-Jan van Ommen * Institut für Klinische Chemie und Laboratoriumsmedizin, Universität Greifswald, Greifswald, Germany. * Henri Wallaschofski * Steno Diabetes Center, Gentofte, Denmark. * Daniel R Witte * Department of Physiatrics, Lapland Central Hospital, Rovaniemi, Finland. * Paavo Zitting * School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, Western Australia, Australia. * John P Beilby * School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia. * Alan L James * Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland. * Mika Kähönen * Department of Clinical Chemistry, University of Tampere and Tampere University Hospital, Tampere, Finland. * Terho Lehtimäki * Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland. * Olli Raitakari * The Department of Clinical Physiology, Turku University Hospital, Turku, Finland. * Olli Raitakari * Department of Medicine, University of Leipzig, Leipzig, Germany. * Michael Stumvoll & * Anke Tönjes * Leipziger Interdisziplin?r Forschungskomplex zu molekularen Ursachen umwelt- und lebensstilassoziierter Erkrankungen (LIFE) Study Centre, University of Leipzig, Leipzig, Germany. * Michael Stumvoll * Coordination Centre for Clinical Trials, University of Leipzig, Leipzig, Germany. * Anke Tönjes * Department of Medicine, University of Turku and Turku University Hospital, Turku, Finland. * Jorma Viikari * INSERM Centre de Recherche en Epidémiologie et Santé des Populations (CESP) U1018, Villejuif, France. * Beverley Balkau * University Paris Sud 11, Unité Mixte de Recherche en Santé (UMRS) 1018, Villejuif, France. * Beverley Balkau * Department of Social Medicine, University of Bristol, Bristol, UK. * Yoav Ben-Shlomo * The London School of Hygiene and Tropical Medicine, London, UK. * Shah Ebrahim * South Asia Network for Chronic Disease, New Delhi, India. * Shah Ebrahim * Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK. * Philippe Froguel * Faculty of Health Science, University of Southern Denmark, Odense, Denmark. * Torben Hansen * Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, Regensburg, Germany. * Christian Hengstenberg * Regensburg University Medical Center, Innere Medizin II, Regensburg, Germany. * Christian Hengstenberg * Department of Social Services and Health Care, Jakobstad, Finland. * Bo Isomaa * Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark. * Torben Jørgensen * Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark. * Torben Jørgensen * NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK. * Fredrik Karpe & * Mark I McCarthy * Department of Endocrinology, Diabetology and Nutrition, Bichat-Claude Bernard University Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France. * Michel Marre * Cardiovascular Genetics Research Unit, Université Henri Poincaré-Nancy 1, Nancy, France. * Michel Marre * Institute of Human Genetics, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany. * Thomas Meitinger * Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. * Thomas Meitinger * Institute of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. * Oluf Pedersen * Faculty of Health Science, University of Aarhus, Aarhus, Denmark. * Oluf Pedersen * Department of Medicine III, Prevention and Care of Diabetes, University of Dresden, Dresden, Germany. * Peter E H Schwarz * Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland. * Tiinamaija Tuomi * Research Program of Molecular Medicine, University of Helsinki, Helsinki, Finland. * Tiinamaija Tuomi * Hjelt Institute, Department of Public Health, University of Helsinki, Helsinki, Finland. * Jaakko Tuomilehto * South Ostrobothnia Central Hospital, Seinajoki, Finland. * Jaakko Tuomilehto * Collaborative Health Studies Coordinating Center, Seattle, Washington, USA. * Alice M Arnold * Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois (CHUV) University Hospital, Lausanne, Switzerland. * Jacques S Beckmann * Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas, USA. * Eric Boerwinkle * Division of Research, Kaiser Permanente Northern California, Oakland, California, USA. * Carlos Iribarren * Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA. * Carlos Iribarren * Department of Epidemiology and Medicine, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. * W H Linda Kao * National Institute for Health and Welfare, Department of Mental Health and Substance Abuse Services, Unit for Child and Adolescent Mental Health, Helsinki, Finland. * Jaakko Kaprio * Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands. * Ben Oostra * Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands. * Brenda W Penninx * Department of Psychiatry, University Medical Centre Groningen, Groningen, The Netherlands. * Brenda W Penninx * Department of Neurology, General Central Hospital, Bolzano, Italy. * Peter P Pramstaller * Department of Neurology, University of Lübeck, Lübeck, Germany. * Peter P Pramstaller * Departments of Epidemiology, Medicine and Health Services, University of Washington, Seattle, Washington, USA. * Bruce M Psaty * Group Health Research Institute, Group Health, Seattle, Washington, USA. * Bruce M Psaty * Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, Maryland, USA. * Alan R Shuldiner * Uppsala University, Department of Medical Sciences, Molecular Medicine, Uppsala, Sweden. * Ann-Christine Syvanen * Institut für Community Medicine, Greifswald, Germany. * Henry Völzke * Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois (CHUV) University Hospital, Lausanne, Switzerland. * Peter Vollenweider * Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, USA. * Ingrid B Borecki * Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. * Talin Haritunians * Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA. * Robert C Kaplan * Carolina Center for Genome Sciences, School of Public Health, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA. * Kari E North * Department of Medical Genetics, University of Helsinki, Helsinki, Finland. * Leena Peltonen * Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland, USA. * David Schlessinger * Division of Community Health Sciences, St George's, University of London, London, UK. * David P Strachan * Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. * Joel N Hirschhorn * Klinikum Grosshadern, Munich, Germany. * H-Erich Wichmann * Ludwig-Maximilians-Universität, Institute of Medical Informatics, Biometry and Epidemiology, Munich, Germany. * H-Erich Wichmann * Faculty of Medicine, University of Iceland, Reykjavík, Iceland. * Unnur Thorsteinsdottir & * Kari Stefansson * University of Cambridge Metabolic Research Labs, Institute of Metabolic Science Addenbrooke's Hospital, Cambridge, UK. * Inês Barroso * Division of Intramural Research, National Heart, Lung, and Blood Institute, Framingham Heart Study, Framingham, Massachusetts, USA. * Caroline S Fox * These authors jointly directed this work. * Kari Stefansson, * L Adrienne Cupples, * Ruth J F Loos, * Inês Barroso, * Mark I McCarthy, * Caroline S Fox, * Karen L Mohlke & * Cecilia M Lindgren Consortia * MAGIC Contributions I.B., C.S.F., I.M.H. (lead), C.M.L. (lead), M.I.M., K.L. Mohlke, L.Q., V. Steinthorsdottir, G.T., M.C.Z. T.L.A., N.B., I.B., L.A.C., C.M.D., C.S.F., T.B.H., I.M.H., A.U.J., C.M.L. (lead), R.J.F.L., R.M., M.I.M., K.L. Mohlke, L.Q., J.C.R., E.K.S., V. Steinthorsdottir, K. Stefansson, G.T., U.T., C.C.W., T.W., T.W.W., H.E.W., M.C.Z. S.I.B., I.M.H. (lead), E.I., A.U.J., H.L., C.M.L. (lead), R.J.F.L. (lead), J.L., R.M., L.Q., J.C.R., E.K.S., G.T., S.V., M.N.W., E.W., C.J.W., T.W.W., T.W. S.I.B., T.E., I.M.H., A.U.J., T.O.K., Z.K., S.L., C.M.L., R.J.F.L., R.M., K.L. Monda, K.E.N., L.Q., J.C.R. (lead), V. Steinthorsdottir, G.T., T.W.W. (lead). S.I.B., A.L.D., C.C.H., J.N.H., F.K., L.M.K., C.M.L., L.L., R.J.F.L., J.L., M.F.M., J.L.M., C.M., G.N., E.E.S., E.K.S., V. Steinthorsdottir, G.T., K.T.Z. : C.M.L., S.A.M., M.I.M., J.N., V. Steinthorsdottir, G.T., B.F.V. S.I.B., I.B.B., N.C., K.E., T.M.F., M.F.F., T.F., M.E.G., J.N.H., E.I., G.L., C.M.L., H.L., R.M., M. Mangino, M.I.M., K.L. Mohlke, D.R.N., J.R.O., S.P., J.R.B.P., J.C.R., A.V.S., E.K.S., P.M.V., M.N.W., C.J.W., R.J.W., E.W., A.R.W., J.Y. G.R.A., D.A., N.A., T.A., T.L.A., N.B., C.C., P.S.C., L.C., L.A.C., D.I.C., M.N.C., C.M.D., T.E., K.E., E.F., M.F.F., T.F., A.P.G., N.L.G., M.E.G., C. Hayward, N.L.H., I.M.H., J.J.H., A.U.J., Å.J., T. Johnson, J.O.J., J.R.K., M. Kaakinen, K. Kapur, S. Ketkar, J.W.K., P. Kraft, A.T.K., Z.K., J. Kettunen, C. Lamina, R.J.F.L., C. Lecoeur, H.L., M.F.L., C.M.L., J.L., R.W.L., R.M., M. Mangino, B.M., K.L. Monda, A.P.M., N.N., K.E.N., D.R.N., J.R.O., K.K.O., C.O., M.J.P., O. Polasek, I. Prokopenko, N.P., M.P., L.Q., J.C.R., N.W.R., S.R., F.R., N.R.R., C.S., L.J.S., K. Silander, E.K.S., K. Stark, S.S., A.V.S., N.S., U.S., V. Steinthorsdottir, D.P.S., I.S., M.L.T., T.M.T., N.J.T., A.T., G.T., A.U., S.V., V. Vitart, L.V., P.M.V., R.M.W., R.W., R.J.W., S.W., M.N.W., C.C.W., C.J.W., T.W.W., A.R.W., J.Y., J.H.Z., M.C.Z. D.A., T.L.A., L.D.A., N.B., I.B., A.J.B., E.B., L.L.B., I.B.B., H.C., D.I.C., I.N.M.D., M. Dei, M.R.E., P.E., K.E., N.B.F., M.F., A.P.G., H.G., C.G., E.J.C.G., C.J.G., T. Hansen, A.L.H., N.H., C. Hayward, A.A.H., J.J.H., F.B.H., D.J.H., J.H., W.I., M.R.J., Å.J., J.O.J., J.W.K., P. Kovacs, A.T.K., H.K.K., J. Kettunen, P. Kraft, R.N.L., C.M.L., R.J.F.L., J.L., M.L.L., M.A.M., M. Mangino, W.L.M., M.I.M., J.B.J.M., M.J.N., M.N., D.R.N., K.K.O., C.O., O. Pedersen, L.P., M.J.P., G.P., A.N.P., N.P., L.Q., N.W.R., F.R., N.R.R., C.S., A.J.S., N.S., A.C.S., M.T., B.T., A.U., G.U., V. Vatin, P.M.V., H.W., P.Z. H.A., P.A., D.A., A.M.A., T.L.A., B.B., S.R.B., R.B., E.B., I.B.B., J.P.B., M. Dörr, C.M.D., P.E., M.F.F., C.S.F., T.M.F., M.F., S.G., J.G., L.C.G., T. Hansen, A.S.H., C. Hengstenberg, A.L.H., A.T.H., K.H.H., A. Hofman, F.B.H., D.J.H., B.I., T.I., T. Jørgensen, P.J., M.R.J., Å.J., A.J., A.L.J., J.O.J., F.K., L.K., J. Kuusisto, K. Kvaloy, R.K., S. Ketkar, J.W.K., I.K., S. Koskinen, V.K., M. Kähönen, P. Kovacs, O.L., R.N.L., B.L., J.L., G.M.L., R.J.F.L., T.L., M. Mangino, M.I.M., C.O., B.M.P., O. Pedersen, C.G.P.P., J.F.P., I. Pichler, K.P., O. Polasek, A.P., L.Q., M.R., I.R., O.R., V. Salomaa, J. Saramies, P.E.H.S., K. Silander, N.J.S., J.H.S., T.D.S., D.P.S., R.S., H.M.S., J. Sinisalo, T.T., A.T., M.U., P.V., C.B.V., L.V., J.V., D.R.W., G.B.W., S.H.W., G.W., J.C.W., A.F.W., L.Z., P.Z. G.R.A., A.M.A., B.B., Y.B.S., R.N.B., H.B., J.S.B., S.B., M.B., E.B., D.I.B., I.B.B., J.P.B., M.J.C., F.S.C., L.A.C., G.D., C.M.D., S.E., G.E., P.F., C.S.F., T.M.F., L.C.G., V.G., U.G., M.E.G., T. Hansen, C. Hengstenberg, K.H., A. Hamsten, T.B.H., A.T.H., A. Hofman, F.B.H., D.J.H., B.I., T.I., C.I., T. Jørgensen, M.R.J., A.L.J., F.K., K.T.K., W.H.L.K., R.K., J. Kaprio, M. Kähönen, M.L., D.A.L., L.J.L., C.M.L., R.J.F.L., T.L., M. Marre, T.M., A.M.E.T., K.M., M.I.M., K.L. Mohlke, P.B.M., K.E.N., M.S.N., D.R.N., B.O., C.O., O. Pedersen, L.P., B.W.P., P.P.P., B.M.P., L.J.P., T.Q., A.R., I.R., O.R., P.M.R., V. Salomaa, P.S., D.S., A.R.S., N.S., T.D.S., K. Stefansson, D.P.S., A.C.S., M.S., T.T., J.T., U.T., A.T., M.U., A.U., T.T.V., P.V., H.V., J.V., P.M.V., N.J.W., H.E.W., J.F.W., J.C.W., A.F.W. G.R.A., T.L.A., I.B., S.I.B., M.B., I.B.B., P.D., C.M.D., C.S.F., T.M.F., L.C.G., T. Haritunians, J.N.H. (chair), D.J.H., E.I., R.K., R.J.F.L., M.I.M., K.L. Mohlke, K.E.N., J.R.O., L.P., D.S., D.P.S., U.T., H.E.W. Competing financial interests I.B. and spouse own stock in Incyte Ltd and GlaxoSmithKline. J.H. is a member of the Scientific Advisory Board, Correlagen, Inc. A.P. is employed by Amgen. K.S., V.S., G.T., U.T. and G.B.W. are employed by deCODE Genetics. Corresponding authors Correspondence to: * Cecilia M Lindgren (celi@well.ox.ac.uk) or * Karen L Mohlke (mohlke@med.unc.edu) or * Caroline S Fox (foxca@nhlbi.nih.gov) or * Mark I McCarthy (mark.mccarthy@drl.ox.ac.uk) or * Iris M Heid (iris.heid@klinik.uni-regensburg.de) Supplementary information * Abstract * Author information * Supplementary information Excel files * Supplementary Table 11 (220K) 3,113 SNPs tagging the 856 CNVs in the HapMap 3 catalog across all HapMap3 populations PDF files * Supplementary Text and Figures (676K) Supplementary Tables 1–11, Supplementary Figure 1 and Supplementary Note. Additional data
• Genome-wide association studies of 14 agronomic traits in rice landraces
  - Nat Genet 42(11):961-967 (2010)
  Nature Genetics | Article Genome-wide association studies of 14 agronomic traits in rice landraces * Xuehui Huang1, 2, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * Xinghua Wei3, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * Tao Sang4, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * Qiang Zhao1, 2, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * Qi Feng1, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * Yan Zhao1 Search for this author in: * NPG journals * PubMed * Google Scholar * Canyang Li1 Search for this author in: * NPG journals * PubMed * Google Scholar * Chuanrang Zhu1 Search for this author in: * NPG journals * PubMed * Google Scholar * Tingting Lu1 Search for this author in: * NPG journals * PubMed * Google Scholar * Zhiwu Zhang5 Search for this author in: * NPG journals * PubMed * Google Scholar * Meng Li5, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Danlin Fan1 Search for this author in: * NPG journals * PubMed * Google Scholar * Yunli Guo1 Search for this author in: * NPG journals * PubMed * Google Scholar * Ahong Wang1 Search for this author in: * NPG journals * PubMed * Google Scholar * Lu Wang1 Search for this author in: * NPG journals * PubMed * Google Scholar * Liuwei Deng1 Search for this author in: * NPG journals * PubMed * Google Scholar * Wenjun Li1 Search for this author in: * NPG journals * PubMed * Google Scholar * Yiqi Lu1 Search for this author in: * NPG journals * PubMed * Google Scholar * Qijun Weng1 Search for this author in: * NPG journals * PubMed * Google Scholar * Kunyan Liu1 Search for this author in: * NPG journals * PubMed * Google Scholar * Tao Huang1 Search for this author in: * NPG journals * PubMed * Google Scholar * Taoying Zhou1 Search for this author in: * NPG journals * PubMed * Google Scholar * Yufeng Jing1 Search for this author in: * NPG journals * PubMed * Google Scholar * Wei Li1 Search for this author in: * NPG journals * PubMed * Google Scholar * Zhang Lin1 Search for this author in: * NPG journals * PubMed * Google Scholar * Edward S Buckler5, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Qian Qian3 Search for this author in: * NPG journals * PubMed * Google Scholar * Qi-Fa Zhang8 Search for this author in: * NPG journals * PubMed * Google Scholar * Jiayang Li9 Search for this author in: * NPG journals * PubMed * Google Scholar * Bin Han1, 2bhan@ncgr.ac.cn Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 42 ,Pages:961–967Year published:(2010)DOI:doi:10.1038/ng.695Received10 May 2010Accepted27 September 2010Published online24 October 2010 Abstract * Abstract * Accession codes * Author information * Supplementary information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Uncovering the genetic basis of agronomic traits in crop landraces that have adapted to various agro-climatic conditions is important to world food security. Here we have identified ~3.6 million SNPs by sequencing 517 rice landraces and constructed a high-density haplotype map of the rice genome using a novel data-imputation method. We performed genome-wide association studies (GWAS) for 14 agronomic traits in the population of Oryza sativa indica subspecies. The loci identified through GWAS explained ~36% of the phenotypic variance, on average. The peak signals at six loci were tied closely to previously identified genes. This study provides a fundamental resource for rice genetics research and breeding, and demonstrates that an approach integrating second-generation genome sequencing and GWAS can be used as a powerful complementary strategy to classical biparental cross-mapping for dissecting complex traits in rice. View full text Figures at a glance * Figure 1: Divergence and geographic origins of 517 rice landraces. () Neighbor-joining tree constructed from simple matching distance of all SNPs. Red, indica; blue, japonica; purple, intermediate. () Comparison of allele frequencies between indica and japonica. For each SNP, we identified the minor allele across all landraces and then calculated the frequency of this allele in indica and japonica. Color index indicates the number of SNPs with each set of allele frequencies. () Genome-wide average LD decay estimated from 373 indica (red) and 131 japonica (blue) landraces. * Figure 2: Population structures of Chinese landraces of both subspecies. () Neighbor-joining tree of 373 indica landraces. The three indica subgroups identified from the tree are color-coded in –. () PCA plots of the first two components of 373 indica landraces. () Geographic origins of landraces of each indica subgroup. () Neighbor-joining tree of 131 japonica landraces. The three japonica subgroups identified from the tree are color-coded in –. () PCA plots of the first two components of 131 japonica landraces. () Geographic origins of landraces of each japonica subgroup. * Figure 3: Influence of populational and experimental factors on the performance of the KNN-based imputation method. Performance of the imputation was evaluated by specificity and filling rate. The specificity of the genotype data set after imputation of missing genotypes was assessed against BAC sequences and high-coverage Illumina data. Filling rate was defined as the non–missing data rate of the genotype data set after imputation. Gray horizontal dashed lines indicate 95%, highlighting different scales used on different panels. () Genomic regions with LD decay range varying from <10 kb to >150 kb in 10-kb intervals. () Sequencing error rates. Various higher error rates were introduced for the simulation. () Sequencing coverage. Sequences were removed to simulate data sets derived from lower sequencing coverage. () Population size. Individuals were randomly removed to create a series of smaller populations for simulation. * Figure 4: Genome-wide association studies of grain width and heading date. () Manhattan plots of the simple model for grain width. Negative log10-transformed P values from a genome-wide scan are plotted against position on each of 12 chromosomes. Blue horizontal dashed line indicates the genome-wide significance threshold. () Quantile-quantile plot of the simple model for grain width. () Manhattan plots of compressed MLM for grain width, as in . () Quantile-quantile plot of compressed MLM for grain width. () Manhattan plots of the simple model for heading date, as in . () Quantile-quantile plot of the simple model for heading date. () Manhattan plots of compressed MLM for heading date, as in . () Quantile-quantile plot of compressed MLM for heading date. * Figure 5: Regions of the genome showing strong association signals near previously identified genes. Top of each panel shows a 0.5-Mb region on each side of the peak SNP (SNP with the lowest P value), whose position is indicated by a vertical red line. Negative log10-transformed P values from the compressed MLM are plotted on the vertical axis; axis scales are slightly different across panels. Blue horizontal dashed lines indicate the genome-wide significance threshold. Bottom of each panel shows a 50-kb region on each side of the peak SNP, with annotated genes indicated by green boxes. Previously identified genes controlling the traits are labeled. Local LDs of the chromosomal regions containing peak SNPs are given. () Apiculus color. () Pericarp color. () Gelatinization temperature. () Amylose content. () Grain width. () Grain length. * Figure 6: Contributions of identified loci to phenotypic variance of each of 14 agronomic traits. Numbers of loci used to assign contributions to phenotypic variance are indicated at ends of bars. Loci from the compressed MLM are listed in Table 1, and loci from the simple model are listed in Supplementary Table 7. Joint loci from both models, with redundancy excluded, are listed in Supplementary Table 8. Accession codes * Abstract * Accession codes * Author information * Supplementary information Referenced accessions GenBank * ERP000106 * ERP000235 * ERP000236 Author information * Abstract * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Xuehui Huang, * Xinghua Wei, * Tao Sang, * Qiang Zhao & * Qi Feng Affiliations * National Center for Gene Research, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. * Xuehui Huang, * Qiang Zhao, * Qi Feng, * Yan Zhao, * Canyang Li, * Chuanrang Zhu, * Tingting Lu, * Danlin Fan, * Yunli Guo, * Ahong Wang, * Lu Wang, * Liuwei Deng, * Wenjun Li, * Yiqi Lu, * Qijun Weng, * Kunyan Liu, * Tao Huang, * Taoying Zhou, * Yufeng Jing, * Wei Li, * Zhang Lin & * Bin Han * CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. * Xuehui Huang, * Qiang Zhao & * Bin Han * State Key Laboratory of Rice Biology, China National Rice Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou, China. * Xinghua Wei & * Qian Qian * Department of Plant Biology, Michigan State University, East Lansing, Michigan, USA. * Tao Sang * Institute for Genomic Diversity, Cornell University, Ithaca, New York, USA. * Zhiwu Zhang, * Meng Li & * Edward S Buckler * National Center for Soybean Improvement, State Key Laboratory of Crop Genetics and Germplasm Enhancement, College of Agriculture, Nanjing Agricultural University, Nanjing, China. * Meng Li * US Department of Agriculture–Agricultural Research Service, Ithaca, New York, USA. * Edward S Buckler * National Key Laboratory of Crop Genetic Improvement, National Center for Plant Gene Research (Wuhan), Huazhong Agricultural University, Wuhan, China. * Qi-Fa Zhang * National Center for Plant Gene Research, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China. * Jiayang Li Contributions B.H. conceived the project and its components. J.L., Q.-F.Z., T.S. and B.H. contributed to the original concept of the project. Q.F., D.F., Y.G., L.D., Wenjun Li, Y.L. and Q.W. performed the genome sequencing. X.H., Q.Z., Y.Z., C.Z., T.L., K.L. and T.H. performed GWAS and data analysis. Y.Z., Q.Z., C.Z. and X.H. developed the imputation program for data analyses. X.H., Y.Z. and T.S. performed statistical simulations. Z.Z., M.L., Y.Z. and E.S.B. performed GWAS using the compressed mixed linear model. X.W., C.L., A.W., L.W., T.Z., Y.J., Wei Li, Z.L. and Q.Q. collected samples and performed the phenotyping. Q.Z., T.L., Y.Z. and X.H. prepared figures and tables. X.H., T.S. and B.H. analyzed all the data and wrote the paper. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Bin Han (bhan@ncgr.ac.cn) Supplementary information * Abstract * Accession codes * Author information * Supplementary information Excel files * Supplementary Table 1 (71K) The list of 517 landrace accessions sampled in this study. * Supplementary Table 5 (31K) The list of genes over-represented for large-effect changes. * Supplementary Table 6 (31K) The list of genes that contained large-effect complete-differentiation SNPs. * Supplementary Table 9 (80K) The genotype dataset of indica landraces on the causal polymorphic sites of three known genes. PDF files * Supplementary Text and Figures (6M) Supplementary Note; Supplementary Tables 2–4, 7 and 8; Supplementary Figs. 1–25 Additional data
• Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants
  - Nat Genet 42(11):969-972 (2010)
  Nature Genetics | Letter Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants * Yingrui Li1, 19 Search for this author in: * NPG journals * PubMed * Google Scholar * Nicolas Vinckenbosch2, 19 Search for this author in: * NPG journals * PubMed * Google Scholar * Geng Tian1, 19 Search for this author in: * NPG journals * PubMed * Google Scholar * Emilia Huerta-Sanchez2, 3, 19 Search for this author in: * NPG journals * PubMed * Google Scholar * Tao Jiang1, 19 Search for this author in: * NPG journals * PubMed * Google Scholar * Hui Jiang1 Search for this author in: * NPG journals * PubMed * Google Scholar * Anders Albrechtsen4 Search for this author in: * NPG journals * PubMed * Google Scholar * Gitte Andersen5 Search for this author in: * NPG journals * PubMed * Google Scholar * Hongzhi Cao1 Search for this author in: * NPG journals * PubMed * Google Scholar * Thorfinn Korneliussen4 Search for this author in: * NPG journals * PubMed * Google Scholar * Niels Grarup5 Search for this author in: * NPG journals * PubMed * Google Scholar * Yiran Guo1 Search for this author in: * NPG journals * PubMed * Google Scholar * Ines Hellman6 Search for this author in: * NPG journals * PubMed * Google Scholar * Xin Jin1, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Qibin Li1 Search for this author in: * NPG journals * PubMed * Google Scholar * Jiangtao Liu1 Search for this author in: * NPG journals * PubMed * Google Scholar * Xiao Liu1 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas Sparsø5 Search for this author in: * NPG journals * PubMed * Google Scholar * Meifang Tang1 Search for this author in: * NPG journals * PubMed * Google Scholar * Honglong Wu1 Search for this author in: * NPG journals * PubMed * Google Scholar * Renhua Wu1 Search for this author in: * NPG journals * PubMed * Google Scholar * Chang Yu1 Search for this author in: * NPG journals * PubMed * Google Scholar * Hancheng Zheng1, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Arne Astrup8 Search for this author in: * NPG journals * PubMed * Google Scholar * Lars Bolund1, 9, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * Johan Holmkvist5 Search for this author in: * NPG journals * PubMed * Google Scholar * Torben Jørgensen11, 12 Search for this author in: * NPG journals * PubMed * Google Scholar * Karsten Kristiansen1, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Ole Schmitz13, 14 Search for this author in: * NPG journals * PubMed * Google Scholar * Thue W Schwartz15 Search for this author in: * NPG journals * PubMed * Google Scholar * Xiuqing Zhang1 Search for this author in: * NPG journals * PubMed * Google Scholar * Ruiqiang Li1, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Huanming Yang1 Search for this author in: * NPG journals * PubMed * Google Scholar * Jian Wang1 Search for this author in: * NPG journals * PubMed * Google Scholar * Torben Hansen5, 16 Search for this author in: * NPG journals * PubMed * Google Scholar * Oluf Pedersen5, 17, 18oluf@hagedorn.dk Search for this author in: * NPG journals * PubMed * Google Scholar * Rasmus Nielsen2, 3, 4rasmus_nielsen@berkeley.edu Search for this author in: * NPG journals * PubMed * Google Scholar * Jun Wang1, 4wangj@genomics.org.cn Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 42 ,Pages:969–972Year published:(2010)DOI:doi:10.1038/ng.680Received08 February 2010Accepted08 September 2010Published online03 October 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Targeted capture combined with massively parallel exome sequencing is a promising approach to identify genetic variants implicated in human traits. We report exome sequencing of 200 individuals from Denmark with targeted capture of 18,654 coding genes and sequence coverage of each individual exome at an average depth of 12-fold. On average, about 95% of the target regions were covered by at least one read. We identified 121,870 SNPs in the sample population, including 53,081 coding SNPs (cSNPs). Using a statistical method for SNP calling and an estimation of allelic frequencies based on our population data, we derived the allele frequency spectrum of cSNPs with a minor allele frequency greater than 0.02. We identified a 1.8-fold excess of deleterious, non-syonomyous cSNPs over synonymous cSNPs in the low-frequency range (minor allele frequencies between 2% and 5%). This excess was more pronounced for X-linked SNPs, suggesting that deleterious substitutions are primarily rece! ssive. View full text Accession codes * Accession codes * Author information * Supplementary information Referenced accessions GenBank * SRA009884 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Yingrui Li, * Nicolas Vinckenbosch, * Geng Tian, * Emilia Huerta-Sanchez & * Tao Jiang Affiliations * BGI-Shenzhen, Shenzhen, China. * Yingrui Li, * Geng Tian, * Tao Jiang, * Hui Jiang, * Hongzhi Cao, * Yiran Guo, * Xin Jin, * Qibin Li, * Jiangtao Liu, * Xiao Liu, * Meifang Tang, * Honglong Wu, * Renhua Wu, * Chang Yu, * Hancheng Zheng, * Lars Bolund, * Karsten Kristiansen, * Xiuqing Zhang, * Ruiqiang Li, * Huanming Yang, * Jian Wang & * Jun Wang * Department of Integrative Biology, University of California Berkeley, Berkeley, California, USA. * Nicolas Vinckenbosch, * Emilia Huerta-Sanchez & * Rasmus Nielsen * Department of Statistics, University of California Berkeley, Berkeley, California, USA. * Emilia Huerta-Sanchez & * Rasmus Nielsen * Department of Biology, University of Copenhagen, Copenhagen, Denmark. * Anders Albrechtsen, * Thorfinn Korneliussen, * Karsten Kristiansen, * Ruiqiang Li, * Rasmus Nielsen & * Jun Wang * Hagedorn Research Institute, Copenhagen, Denmark. * Gitte Andersen, * Niels Grarup, * Thomas Sparsø, * Johan Holmkvist, * Torben Hansen & * Oluf Pedersen * Department of Mathematics, University of Vienna, Vienna, Austria. * Ines Hellman * School of Bioscience and Biotechnology, South China University of Technology, Guangzhou, China. * Xin Jin & * Hancheng Zheng * Department of Human Nutrition, Faculty of Life Sciences, University of Copenhagen, Copenhagen, Denmark. * Arne Astrup * Institute of Human Genetics, University of Aarhus, Aarhus, Denmark. * Lars Bolund * Danish Center for Translational Breast Cancer Research, Copenhagen, Denmark. * Lars Bolund * Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark. * Torben Jørgensen * Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark. * Torben Jørgensen * Department of Endocrinology and Diabetes, Aarhus University Hospital, Aarhus, Denmark. * Ole Schmitz * Department of Clinical Pharmacology, University of Aarhus, Aarhus, Denmark. * Ole Schmitz * Laboratory for Molecular Pharmacology, University of Copenhagen, Copenhagen, Denmark. * Thue W Schwartz * Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark. * Torben Hansen * Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark. * Oluf Pedersen * Institute of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. * Oluf Pedersen Contributions LuCamp was founded and is managed by O.P., Jun Wang, R.N., T.H., G.A., L.B., O.S., T. Lauritzen, K.K., T. Jørgensen, A. Astrup, T.W.S. and A. Albrechtsen. Y.L., N.V., G.T., E.H.-S. and T. Jiang contributed equally to this work. H.Y., Jian Wang, O.P. and Jun Wang managed the present project. Jun Wang, R.N., O.P. and Y.L. designed the analyses. O.P., T.H. and T. Jørgensen recruited the volunteers and prepared the DNA samples. Jun Wang, R.N., Y.L., N.V., E.H.-S., T. Jiang, A. Albrechtsen, H.C., T.K., Y.G., X.J., Q.L., H.W., C.Y., H.Z. and O.P. performed the data analyses. G.T., H.J., J.L., X.L., M.T., R.W. and X.Z. performed sequencing and Sequenom genotyping. Jun Wang, R.N., O.P., N.V., E.H.-S. and Y.L. wrote the first manuscript. All authors contributed to the final manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Jun Wang (wangj@genomics.org.cn) or * Rasmus Nielsen (rasmus_nielsen@berkeley.edu) or * Oluf Pedersen (oluf@hagedorn.dk) Supplementary information * Accession codes * Author information * Supplementary information Excel files * Supplementary Table 1 (20K) Detailed data production information for each sample. * Supplementary Table 3 (392K) Sequenom iPex genotyping results and sequencing results of each sample individual at genotyped sites. * Supplementary Table 5 (32K) Putative extrapolation estimation of SNP counts in each individual. PDF files * Supplementary Text and Figures (592K) Supplementary Tables 2,4,6 and 7, Supplementary Figures 1–3 and Supplementary Note Additional data
• Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33
  - Nat Genet 42(11):973-977 (2010)
  Nature Genetics | Letter Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33 * Richard S Houlston1richard.houlston@icr.ac.uk Search for this author in: * NPG journals * PubMed * Google Scholar * Jeremy Cheadle2 Search for this author in: * NPG journals * PubMed * Google Scholar * Sara E Dobbins1 Search for this author in: * NPG journals * PubMed * Google Scholar * Albert Tenesa3 Search for this author in: * NPG journals * PubMed * Google Scholar * Angela M Jones4 Search for this author in: * NPG journals * PubMed * Google Scholar * Kimberley Howarth4 Search for this author in: * NPG journals * PubMed * Google Scholar * Sarah L Spain4 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Broderick1 Search for this author in: * NPG journals * PubMed * Google Scholar * Enric Domingo4 Search for this author in: * NPG journals * PubMed * Google Scholar * Susan Farrington3 Search for this author in: * NPG journals * PubMed * Google Scholar * James G D Prendergast3 Search for this author in: * NPG journals * PubMed * Google Scholar * Alan M Pittman1 Search for this author in: * NPG journals * PubMed * Google Scholar * Evi Theodoratou3 Search for this author in: * NPG journals * PubMed * Google Scholar * Christopher G Smith2 Search for this author in: * NPG journals * PubMed * Google Scholar * Bianca Olver1 Search for this author in: * NPG journals * PubMed * Google Scholar * Axel Walther4 Search for this author in: * NPG journals * PubMed * Google Scholar * Rebecca A Barnetson3 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Churchman4 Search for this author in: * NPG journals * PubMed * Google Scholar * Emma E M Jaeger4 Search for this author in: * NPG journals * PubMed * Google Scholar * Steven Penegar1 Search for this author in: * NPG journals * PubMed * Google Scholar * Ella Barclay4 Search for this author in: * NPG journals * PubMed * Google Scholar * Lynn Martin4 Search for this author in: * NPG journals * PubMed * Google Scholar * Maggie Gorman4 Search for this author in: * NPG journals * PubMed * Google Scholar * Rachel Mager5 Search for this author in: * NPG journals * PubMed * Google Scholar * Elaine Johnstone5 Search for this author in: * NPG journals * PubMed * Google Scholar * Rachel Midgley5 Search for this author in: * NPG journals * PubMed * Google Scholar * Iina Niittymäki6 Search for this author in: * NPG journals * PubMed * Google Scholar * Sari Tuupanen6 Search for this author in: * NPG journals * PubMed * Google Scholar * James Colley2 Search for this author in: * NPG journals * PubMed * Google Scholar * Shelley Idziaszczyk2 Search for this author in: * NPG journals * PubMed * Google Scholar * The COGENT Consortium16 * Huw J W Thomas7 Search for this author in: * NPG journals * PubMed * Google Scholar * Anneke M Lucassen8 Search for this author in: * NPG journals * PubMed * Google Scholar * D Gareth R Evans9 Search for this author in: * NPG journals * PubMed * Google Scholar * Eamonn R Maher10 Search for this author in: * NPG journals * PubMed * Google Scholar * The CORGI Consortium16 * The COIN Collaborative Group16 * The COINB Collaborative Group16 * Timothy Maughan11 Search for this author in: * NPG journals * PubMed * Google Scholar * Antigone Dimas4, 12 Search for this author in: * NPG journals * PubMed * Google Scholar * Emmanouil Dermitzakis12 Search for this author in: * NPG journals * PubMed * Google Scholar * Jean-Baptiste Cazier4 Search for this author in: * NPG journals * PubMed * Google Scholar * Lauri A Aaltonen6 Search for this author in: * NPG journals * PubMed * Google Scholar * Paul Pharoah13 Search for this author in: * NPG journals * PubMed * Google Scholar * David J Kerr5, 14 Search for this author in: * NPG journals * PubMed * Google Scholar * Luis G Carvajal-Carmona4 Search for this author in: * NPG journals * PubMed * Google Scholar * Harry Campbell15 Search for this author in: * NPG journals * PubMed * Google Scholar * Malcolm G Dunlop3malcolm.dunlop@hgu.mrc.ac.uk Search for this author in: * NPG journals * PubMed * Google Scholar * Ian P M Tomlinson4iant@well.ox.ac.uk Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 42 ,Pages:973–977Year published:(2010)DOI:doi:10.1038/ng.670Received09 April 2010Accepted01 September 2010Published online24 October 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Genome-wide association studies (GWAS) have identified ten loci harboring common variants that influence risk of developing colorectal cancer (CRC). To enhance the power to identify additional CRC risk loci, we conducted a meta-analysis of three GWAS from the UK which included a total of 3,334 affected individuals (cases) and 4,628 controls followed by multiple validation analyses including a total of 18,095 cases and 20,197 controls. We identified associations at four new CRC risk loci: 1q41 (rs6691170, odds ratio (OR) = 1.06, P = 9.55 × 10−10 and rs6687758, OR = 1.09, P = 2.27 × 10−9), 3q26.2 (rs10936599, OR = 0.93, P = 3.39 × 10−8), 12q13.13 (rs11169552, OR = 0.92, P = 1.89 × 10−10 and rs7136702, OR = 1.06, P = 4.02 × 10−8) and 20q13.33 (rs4925386, OR = 0.93, P = 1.89 × 10−10). In addition to identifying new CRC risk loci, this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered. View full text Figures at a glance * Figure 1: Overall study design. * Figure 2: Forest plots of effect size and direction for the six SNPs associated with CRC. Boxes denote allelic OR point estimates with their areas being proportional to the inverse variance weight of the estimate. Horizontal lines represent 95% CIs. The diamond (and broken line) represents the summary OR computed under a fixed effects model, with the 95% CI indicated by its width. The unbroken vertical line is at the null value (OR = 1.0). * Figure 3: Regional plots. (–) Maps of the 1q41 (), 3q26.2 (), 12q13.13 () and 20q13.33 () regions showing evidence of association with CRC and local LD structure. In the association plot, each point represents a SNP genotyped at this locus. For each SNP at the position (kb) shown on the x axis, −log10P from the allelic association test is indicated on the y axis. The recombination rate is shown in blue. The SNP with the strongest association in each region is shown as a red diamond. Data were derived from the combined analysis of the VQ58, UK1, Scotland1, UK2 and Scotland2 cohorts, which resulted in relatively few SNPs being shown for each region but which illustrates the rationale for the selection of SNPs for genotyping in the validation sample sets. In the LD plots (lower), derived from HapMap CEU individuals in Haploview, the color intensity of each SNP represents the strength of LD according to the standard Haploview scheme for r2 (with black indicating values >0.90 through shades of gray to! white, which indicate a value of 0.0). Physical positions are based on NCBI build 36 of the human genome. Author information * Author information * Supplementary information Affiliations * Section of Cancer Genetics, Institute of Cancer Research, Sutton, UK. * Richard S Houlston, * Sara E Dobbins, * Peter Broderick, * Alan M Pittman, * Bianca Olver & * Steven Penegar * Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK. * Jeremy Cheadle, * Christopher G Smith, * James Colley & * Shelley Idziaszczyk * Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and Medical Research Council Human Genetics Unit, Edinburgh, UK. * Albert Tenesa, * Susan Farrington, * James G D Prendergast, * Evi Theodoratou, * Rebecca A Barnetson & * Malcolm G Dunlop * Wellcome Trust Centre for Human Genetics, Oxford, UK. * Angela M Jones, * Kimberley Howarth, * Sarah L Spain, * Enric Domingo, * Axel Walther, * Michael Churchman, * Emma E M Jaeger, * Ella Barclay, * Lynn Martin, * Maggie Gorman, * Antigone Dimas, * Jean-Baptiste Cazier, * Luis G Carvajal-Carmona & * Ian P M Tomlinson * Department of Clinical Pharmacology, Oxford University, Radcliffe Infirmary, Old Road Campus Research Building, Headington, Oxford, UK. * Rachel Mager, * Elaine Johnstone, * Rachel Midgley & * David J Kerr * Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland. * Iina Niittymäki, * Sari Tuupanen & * Lauri A Aaltonen * Colorectal Cancer Unit, Cancer Research UK, St. Mark′s Hospital, Harrow, UK. * Huw J W Thomas * Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK. * Anneke M Lucassen * Medical Genetics, St. Mary's Hospital, Manchester, UK. * D Gareth R Evans * Department of Medical and Molecular Genetics, School of Clinical and Experimental Medicine, University of Birmingham, Institute of Biomedical Research and West Midlands Regional Genetics Service, Birmingham Women's Hospital, Edgbaston, Birmingham, UK. * Eamonn R Maher * Department of Oncology and Palliative Care, School of Medicine, Cardiff University, Heath Park, Cardiff, UK. * Timothy Maughan * Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland. * Antigone Dimas & * Emmanouil Dermitzakis * Cancer Research UK Laboratories, Strangeways Research Laboratory Department of Oncology, University of Cambridge, Cambridge, UK. * Paul Pharoah * Sidra Medical and Research Center, Qatar Foundation, Doha, Qatar. * David J Kerr * Public Health Sciences, University of Edinburgh, Edinburgh, UK. * Harry Campbell * A full list of members is provided in the Supplementary Note. * The COGENT Consortium, * The CORGI Consortium, * The COIN Collaborative Group & * The COINB Collaborative Group Consortia * The COGENT Consortium * The CORGI Consortium * The COIN Collaborative Group * The COINB Collaborative Group Contributions The study was designed and financial support was obtained by R.S.H., I.P.M.T., M.G.D. and H.C. The manuscript was drafted by I.P.M.T., R.S.H. and M.G.D. Statistical and bioinformatic analyses were conducted by S.E.D., S.L.S. and A.T., with contributions from I.P.M.T., J.-B.C. and R.S.H. Oxford and local collaborators: subject recruitment and sample acquisition were done by E.B., M.G., L.M., A.M.L., D.G.R.E., E.R.M., H.J.W.T. and members of the CORGI Consortium, and by R. Mager, R. Midgley, E.J. and D.J.K. Sample preparation was performed by K.H., S.L.S. and E.E.M.J. Genotyping was performed and coordinated by L.G.C.-C., K.H., A.M.J., M.C., E.E.M.J., A.W. and E. Domingo. A.D. and E. Dermitzakis supplied eQTL data. Institute of Cancer Research and local collaborators: subject recruitment and sample acquisition to NSCCG were undertaken by S.P. The coordination of sample preparation and genotyping was performed by P.B. Sample preparation and genotyping were performed by A.M.P. and B.O. Colon Cancer Genetics Group, Edinburgh and local collaborators: subject recruitment and sample acquisition were performed by S.F. and members of the SOCCS and COGS study teams. Sample preparation was coordinated by S.F. Genotyping was performed and coordinated by S.F., E.T., R.A.B. and M.G.D. J.G.D.P. performed the bioinformatic analyses. The following authors from collaborating groups conceived the local or national study, undertook assembly of case-control series in their respective regions, collected data and samples and variously undertook genotyping and analysis: C.G.S., J. Colley, S.I., T.M. and J. Cheadle in Cardiff; I.N., S.T. and L.A.A. in Finland; and P.P. in Cambridge. All other authors undertook sample collection and phenotype data collection and collation in the respective centers. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Richard S Houlston (richard.houlston@icr.ac.uk) or * Malcolm G Dunlop (malcolm.dunlop@hgu.mrc.ac.uk) or * Ian P M Tomlinson (iant@well.ox.ac.uk) Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (324K) Supplementary Tables 1 and 2, Supplementary Figures 1–3 and Supplementary Note Additional data
• A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci
  - Nat Genet 42(11):978-984 (2010)
  Nature Genetics | Letter A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci * Nathaniel Rothman1, 67 Search for this author in: * NPG journals * PubMed * Google Scholar * Montserrat Garcia-Closas1, 67montse.garciaclosas@icr.ac.uk Search for this author in: * NPG journals * PubMed * Google Scholar * Nilanjan Chatterjee1, 67 Search for this author in: * NPG journals * PubMed * Google Scholar * Nuria Malats2, 67 Search for this author in: * NPG journals * PubMed * Google Scholar * Xifeng Wu3, 67 Search for this author in: * NPG journals * PubMed * Google Scholar * Jonine D Figueroa1, 68 Search for this author in: * NPG journals * PubMed * Google Scholar * Francisco X Real2, 4, 68 Search for this author in: * NPG journals * PubMed * Google Scholar * David Van Den Berg5, 68 Search for this author in: * NPG journals * PubMed * Google Scholar * Giuseppe Matullo6, 7, 68 Search for this author in: * NPG journals * PubMed * Google Scholar * Dalsu Baris1, 68 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Thun8, 68 Search for this author in: * NPG journals * PubMed * Google Scholar * Lambertus A Kiemeney9, 10, 11, 68 Search for this author in: * NPG journals * PubMed * Google Scholar * Paolo Vineis7, 12, 68 Search for this author in: * NPG journals * PubMed * Google Scholar * Immaculata De Vivo13, 68 Search for this author in: * NPG journals * PubMed * Google Scholar * Demetrius Albanes1, 68 Search for this author in: * NPG journals * PubMed * Google Scholar * Mark P Purdue1, 68 Search for this author in: * NPG journals * PubMed * Google Scholar * Thorunn Rafnar14, 68 Search for this author in: * NPG journals * PubMed * Google Scholar * Michelle A T Hildebrandt3, 68 Search for this author in: * NPG journals * PubMed * Google Scholar * Anne E Kiltie15, 68 Search for this author in: * NPG journals * PubMed * Google Scholar * Olivier Cussenot16, 17, 68 Search for this author in: * NPG journals * PubMed * Google Scholar * Klaus Golka18, 68 Search for this author in: * NPG journals * PubMed * Google Scholar * Rajiv Kumar19, 68 Search for this author in: * NPG journals * PubMed * Google Scholar * Jack A Taylor20, 68 Search for this author in: * NPG journals * PubMed * Google Scholar * Jose I Mayordomo21, 68 Search for this author in: * NPG journals * PubMed * Google Scholar * Kevin B Jacobs22, 68 Search for this author in: * NPG journals * PubMed * Google Scholar * Manolis Kogevinas23, 24, 25, 26, 68 Search for this author in: * NPG journals * PubMed * Google Scholar * Amy Hutchinson22 Search for this author in: * NPG journals * PubMed * Google Scholar * Zhaoming Wang22 Search for this author in: * NPG journals * PubMed * Google Scholar * Yi-Ping Fu1 Search for this author in: * NPG journals * PubMed * Google Scholar * Ludmila Prokunina-Olsson1 Search for this author in: * NPG journals * PubMed * Google Scholar * Laurie Burdett22 Search for this author in: * NPG journals * PubMed * Google Scholar * Meredith Yeager22 Search for this author in: * NPG journals * PubMed * Google Scholar * William Wheeler27 Search for this author in: * NPG journals * PubMed * Google Scholar * Adonina Tardón25, 28 Search for this author in: * NPG journals * PubMed * Google Scholar * Consol Serra29 Search for this author in: * NPG journals * PubMed * Google Scholar * Alfredo Carrato30 Search for this author in: * NPG journals * PubMed * Google Scholar * Reina García-Closas31 Search for this author in: * NPG journals * PubMed * Google Scholar * Josep Lloreta32 Search for this author in: * NPG journals * PubMed * Google Scholar * Alison Johnson33 Search for this author in: * NPG journals * PubMed * Google Scholar * Molly Schwenn34 Search for this author in: * NPG journals * PubMed * Google Scholar * Margaret R Karagas35 Search for this author in: * NPG journals * PubMed * Google Scholar * Alan Schned35 Search for this author in: * NPG journals * PubMed * Google Scholar * Gerald Andriole Jr36 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert Grubb III36 Search for this author in: * NPG journals * PubMed * Google Scholar * Amanda Black1 Search for this author in: * NPG journals * PubMed * Google Scholar * Eric J Jacobs8 Search for this author in: * NPG journals * PubMed * Google Scholar * W Ryan Diver8 Search for this author in: * NPG journals * PubMed * Google Scholar * Susan M Gapstur8 Search for this author in: * NPG journals * PubMed * Google Scholar * Stephanie J Weinstein1 Search for this author in: * NPG journals * PubMed * Google Scholar * Jarmo Virtamo37 Search for this author in: * NPG journals * PubMed * Google Scholar * Victoria K Cortessis5 Search for this author in: * NPG journals * PubMed * Google Scholar * Manuela Gago-Dominguez5 Search for this author in: * NPG journals * PubMed * Google Scholar * Malcolm C Pike5, 38 Search for this author in: * NPG journals * PubMed * Google Scholar * Mariana C Stern5 Search for this author in: * NPG journals * PubMed * Google Scholar * Jian-Min Yuan39 Search for this author in: * NPG journals * PubMed * Google Scholar * David J Hunter40 Search for this author in: * NPG journals * PubMed * Google Scholar * Monica McGrath40 Search for this author in: * NPG journals * PubMed * Google Scholar * Colin P Dinney41 Search for this author in: * NPG journals * PubMed * Google Scholar * Bogdan Czerniak42 Search for this author in: * NPG journals * PubMed * Google Scholar * Meng Chen3 Search for this author in: * NPG journals * PubMed * Google Scholar * Hushan Yang3 Search for this author in: * NPG journals * PubMed * Google Scholar * Sita H Vermeulen9, 43 Search for this author in: * NPG journals * PubMed * Google Scholar * Katja K Aben9, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * J Alfred Witjes11 Search for this author in: * NPG journals * PubMed * Google Scholar * Remco R Makkinje43 Search for this author in: * NPG journals * PubMed * Google Scholar * Patrick Sulem14 Search for this author in: * NPG journals * PubMed * Google Scholar * Soren Besenbacher14 Search for this author in: * NPG journals * PubMed * Google Scholar * Kari Stefansson14, 44 Search for this author in: * NPG journals * PubMed * Google Scholar * Elio Riboli12 Search for this author in: * NPG journals * PubMed * Google Scholar * Paul Brennan45 Search for this author in: * NPG journals * PubMed * Google Scholar * Salvatore Panico46 Search for this author in: * NPG journals * PubMed * Google Scholar * Carmen Navarro25, 47 Search for this author in: * NPG journals * PubMed * Google Scholar * Naomi E Allen48 Search for this author in: * NPG journals * PubMed * Google Scholar * H Bas Bueno-de-Mesquita49 Search for this author in: * NPG journals * PubMed * Google Scholar * Dimitrios Trichopoulos50, 51 Search for this author in: * NPG journals * PubMed * Google Scholar * Neil Caporaso1 Search for this author in: * NPG journals * PubMed * Google Scholar * Maria Teresa Landi1 Search for this author in: * NPG journals * PubMed * Google Scholar * Federico Canzian52 Search for this author in: * NPG journals * PubMed * Google Scholar * Borje Ljungberg53 Search for this author in: * NPG journals * PubMed * Google Scholar * Anne Tjonneland54 Search for this author in: * NPG journals * PubMed * Google Scholar * Francoise Clavel-Chapelon55 Search for this author in: * NPG journals * PubMed * Google Scholar * David T Bishop56 Search for this author in: * NPG journals * PubMed * Google Scholar * Mark T W Teo56 Search for this author in: * NPG journals * PubMed * Google Scholar * Margaret A Knowles56 Search for this author in: * NPG journals * PubMed * Google Scholar * Simonetta Guarrera7 Search for this author in: * NPG journals * PubMed * Google Scholar * Silvia Polidoro7 Search for this author in: * NPG journals * PubMed * Google Scholar * Fulvio Ricceri6, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Carlotta Sacerdote7, 57 Search for this author in: * NPG journals * PubMed * Google Scholar * Alessandra Allione7 Search for this author in: * NPG journals * PubMed * Google Scholar * Geraldine Cancel-Tassin17 Search for this author in: * NPG journals * PubMed * Google Scholar * Silvia Selinski18 Search for this author in: * NPG journals * PubMed * Google Scholar * Jan G Hengstler18 Search for this author in: * NPG journals * PubMed * Google Scholar * Holger Dietrich58 Search for this author in: * NPG journals * PubMed * Google Scholar * Tony Fletcher59 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Rudnai60 Search for this author in: * NPG journals * PubMed * Google Scholar * Eugen Gurzau61 Search for this author in: * NPG journals * PubMed * Google Scholar * Kvetoslava Koppova62 Search for this author in: * NPG journals * PubMed * Google Scholar * Sophia C E Bolick20 Search for this author in: * NPG journals * PubMed * Google Scholar * Ashley Godfrey20 Search for this author in: * NPG journals * PubMed * Google Scholar * Zongli Xu20 Search for this author in: * NPG journals * PubMed * Google Scholar * José I Sanz-Velez63 Search for this author in: * NPG journals * PubMed * Google Scholar * María D García-Prats63 Search for this author in: * NPG journals * PubMed * Google Scholar * Manuel Sanchez21 Search for this author in: * NPG journals * PubMed * Google Scholar * Gabriel Valdivia21 Search for this author in: * NPG journals * PubMed * Google Scholar * Stefano Porru64 Search for this author in: * NPG journals * PubMed * Google Scholar * Simone Benhamou65, 66 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert N Hoover1 Search for this author in: * NPG journals * PubMed * Google Scholar * Joseph F Fraumeni Jr1 Search for this author in: * NPG journals * PubMed * Google Scholar * Debra T Silverman1, 69 Search for this author in: * NPG journals * PubMed * Google Scholar * Stephen J Chanock1, 69 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 42 ,Pages:978–984Year published:(2010)DOI:doi:10.1038/ng.687Received10 May 2010Accepted19 August 2010Published online24 October 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10−12) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10−11) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10−7) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10−11) and a tag SNP for NAT2 acetylation status (P = 4 × 10−11), and found interactions with smoking in both regions. Our findings on common variants associ! ated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis. View full text Figures at a glance * Figure 1: Study design of a multi-stage GWAS of bladder cancer. See Online Methods and Supplementary Table 1 for details of study designs and sample sizes. *The tag SNP, rs1495741 located 3′ of NAT2 (ref. 26) was genotyped in subjects in stage 2 and stage 3 studies, as well as on the Illumina bead chips used in stage 1. **Includes 338 additional cases from Nijmegen Bladder Cancer Study that were added to the final combined analyses. QC, quality control. * Figure 2: Association results, recombination and linkage disequilibrium plots for four regions on chromosomes 22q13.1, 19q12, 2q37.1 and 8p22. Association results of stage 1 (green circles), combined stages 2 and 3 (blue triangles) and combined data from the three stages (red diamonds) are shown in the top panel with −log10P values (left y axis). Overlaid on these panels for each locus are the likelihood ratio statistics (right y axis) to estimate putative recombination hotspot across the region based on five sets of 100 randomly selected control samples (connected lines in various colors). Pairwise r2 values based on control populations are displayed at the bottom for all SNPs included in the GWAS analysis. () The chromosome 22q13.1 region spanning 37,617,065–37,743,614. () The region of chromosome 19q12 spanning 34,922,089–35,080,325. () The region of 2q37.1 spanning 234,131,582–234,286,564. () The region of 8p22 spanning 18,216,291–18,406,519. Genomic coordinates are based on NCBI Human Genome Build 36.3. Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Nathaniel Rothman, * Montserrat Garcia-Closas, * Nilanjan Chatterjee, * Nuria Malats & * Xifeng Wu Affiliations * Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA. * Nathaniel Rothman, * Montserrat Garcia-Closas, * Nilanjan Chatterjee, * Jonine D Figueroa, * Dalsu Baris, * Demetrius Albanes, * Mark P Purdue, * Yi-Ping Fu, * Ludmila Prokunina-Olsson, * Amanda Black, * Stephanie J Weinstein, * Neil Caporaso, * Maria Teresa Landi, * Robert N Hoover, * Joseph F Fraumeni Jr, * Debra T Silverman & * Stephen J Chanock * Spanish National Cancer Research Centre, Madrid, Spain. * Nuria Malats & * Francisco X Real * Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. * Xifeng Wu, * Michelle A T Hildebrandt, * Meng Chen & * Hushan Yang * Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain. * Francisco X Real * Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. * David Van Den Berg, * Victoria K Cortessis, * Manuela Gago-Dominguez, * Malcolm C Pike & * Mariana C Stern * Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy. * Giuseppe Matullo & * Fulvio Ricceri * Human Genetics Foundation (HuGeF), Torino, Italy. * Giuseppe Matullo, * Paolo Vineis, * Simonetta Guarrera, * Silvia Polidoro, * Fulvio Ricceri, * Carlotta Sacerdote & * Alessandra Allione * Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA. * Michael Thun, * Eric J Jacobs, * W Ryan Diver & * Susan M Gapstur * Department of Epidemiology, Biostatistics and Health Technology Assessment, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Lambertus A Kiemeney, * Sita H Vermeulen & * Katja K Aben * Comprehensive Cancer Center East, Nijmegen, The Netherlands. * Lambertus A Kiemeney & * Katja K Aben * Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Lambertus A Kiemeney & * J Alfred Witjes * Imperial College London, London, UK. * Paolo Vineis & * Elio Riboli * Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. * Immaculata De Vivo * deCODE Genetics, Reykjavik, Iceland. * Thorunn Rafnar, * Patrick Sulem, * Soren Besenbacher & * Kari Stefansson * Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK. * Anne E Kiltie * Department of Urology, Assistance Publique-Hôpitaux de Paris, Tenon Hospital, Paris, France. * Olivier Cussenot * Centre de Recherche sur les Pathologies Prostatiques, Paris, France. * Olivier Cussenot & * Geraldine Cancel-Tassin * Leibniz Research Centre for Working Environment and Human Factors, Dortmund, Germany. * Klaus Golka, * Silvia Selinski & * Jan G Hengstler * Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany. * Rajiv Kumar * National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA. * Jack A Taylor, * Sophia C E Bolick, * Ashley Godfrey & * Zongli Xu * University of Zaragoza, Zaragoza, Spain. * Jose I Mayordomo, * Manuel Sanchez & * Gabriel Valdivia * Core Genotype Facility, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, Maryland, USA. * Kevin B Jacobs, * Amy Hutchinson, * Zhaoming Wang, * Laurie Burdett & * Meredith Yeager * Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain. * Manolis Kogevinas * Municipal Institute of Medical Research, Barcelona, Spain. * Manolis Kogevinas * CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain. * Manolis Kogevinas, * Adonina Tardón & * Carmen Navarro * National School of Public Health, Athens, Greece. * Manolis Kogevinas * Information Management Services, Inc., Rockville, Maryland, USA. * William Wheeler * Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain. * Adonina Tardón * Universitat Pompeu Fabra, Barcelona, Spain. * Consol Serra * Ramón y Cajal University Hospital, Madrid, Spain. * Alfredo Carrato * Unidad de Investigación, Hospital Universitario de Canarias, La Laguna, Spain. * Reina García-Closas * Hospital del Mar-Institut Municipal d'Investigació Mèdica (IMIM), Universitat Pompeu Fabra, Barcelona, Spain. * Josep Lloreta * Vermont Cancer Registry, Burlington, Vermont, USA. * Alison Johnson * Maine Cancer Registry, Augusta, Maine, USA. * Molly Schwenn * Dartmouth Medical School, Hanover, New Hampshire, USA. * Margaret R Karagas & * Alan Schned * Department of Urology, Washington University School of Medicine, St. Louis, Missouri, USA. * Gerald Andriole Jr & * Robert Grubb III * National Institute for Health and Welfare, Helsinki, Finland. * Jarmo Virtamo * Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. * Malcolm C Pike * Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA. * Jian-Min Yuan * Department of Epidemiology, Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. * David J Hunter & * Monica McGrath * Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. * Colin P Dinney * Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. * Bogdan Czerniak * Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Sita H Vermeulen & * Remco R Makkinje * Faculty of Medicine, University of Iceland, Reykjavik, Iceland. * Kari Stefansson * International Agency for Research on Cancer, Lyon, France. * Paul Brennan * Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy. * Salvatore Panico * Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain. * Carmen Navarro * Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. * Naomi E Allen * National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. * H Bas Bueno-de-Mesquita * Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. * Dimitrios Trichopoulos * Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece. * Dimitrios Trichopoulos * Genomic Epidemiology Group, German Cancer Research Center, Heidelberg, Germany. * Federico Canzian * Department of Surgical and Perioperative Sciences, University of Umea, Umea, Sweden. * Borje Ljungberg * Danish Cancer Society, Institute of Cancer Epidemiology, Copenhagen, Denmark. * Anne Tjonneland * Centre for Research in Epidemiology and Population Health, Institute Gustave-Roussy, Paris South University, Villejuif, France. * Francoise Clavel-Chapelon * Leeds Institute of Molecular Medicine, St. James's University Hospital, University of Leeds, Leeds, UK. * David T Bishop, * Mark T W Teo & * Margaret A Knowles * Unit of Cancer Epidemiology, University of Torino, Torino, Italy. * Carlotta Sacerdote * Department of Urology, Paul Gerhardt Foundation, Wittenberg, Germany. * Holger Dietrich * Institute of Hygiene and Tropical Medicine, London, UK. * Tony Fletcher * National Institute of Environmental Health, Budapest, Hungary. * Peter Rudnai * Babes Bolyai University, Environmental Health Center, Cluj-Napoca, Romania. * Eugen Gurzau * State Health Institute, Banská Bystrica, Slovakia. * Kvetoslava Koppova * San Jorge University Hospital, Huesca, Spain. * José I Sanz-Velez & * María D García-Prats * Department of Experimental and Applied Medicine, Section of Occupational Medicine and Industrial Hygiene, University of Brescia, Brescia, Italy. * Stefano Porru * Institut national de la santé et de la recherche médicale, U946, Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain (CEPH), Paris, France. * Simone Benhamou * Centre National de la Recherche Scientifique, UMR8200, Institut Gustave-Roussy, Villejuif, France. * Simone Benhamou * These authors are the designated representatives of the participating studies. * Jonine D Figueroa, * Francisco X Real, * David Van Den Berg, * Giuseppe Matullo, * Dalsu Baris, * Michael Thun, * Lambertus A Kiemeney, * Paolo Vineis, * Immaculata De Vivo, * Demetrius Albanes, * Mark P Purdue, * Thorunn Rafnar, * Michelle A T Hildebrandt, * Anne E Kiltie, * Olivier Cussenot, * Klaus Golka, * Rajiv Kumar, * Jack A Taylor, * Jose I Mayordomo, * Kevin B Jacobs & * Manolis Kogevinas * These authors jointly directed this work. * Debra T Silverman & * Stephen J Chanock Contributions N.R., M.G.-C., N.C., J.D.F., D.T.S. and S.J.C. organized and designed the study.S.J.C., K.B.J., A.H., Z.W., Y.-P.F., .L.P.-O., L.B., X.W., M.A.T.H., M.C., D.V.D.B., S.G., S.P., R.R.M., I.D.V., T.R., D.T.B., G.C.-T., J.G.H., R.K., S.C.E.B. and A.G. conducted and supervised genotyping of samples. M.G.-C., N.C., N.R., K.B.J., M.Y., N.M., D.T.S. and S.J.C. contributed to the design and execution of statistical analysis. M.G.-C., N.R., N.C., N.M., J.D.F., F.X.R., J.F.F., D.T.S. and S.J.C. wrote the first draft of the manuscript.N.R., M.G.-C., N.M., X.W., J.D.F., F.X.R., D.V.D.B., F.X.R., G.M., D.B., M.T., L.A.K., P.V., I.D.V., D.A., M.P.P., T.R., M.A.T.H., A.E.K., O.C., K.G., R.K., J.A.T., J.I.M., M.K., A.T., C.S., A.C., R.G.-C., J.L., A.J., M.S., M.R.K., A.S., G.A., R.G., A.B., E.J.J., W.R.D., S.M.G., S.J.W., J.V., V.K.C., M.G.-D., M.C.P., M.C.S., J.-M.Y., D.J.H., M.M., C.P.D., B.C., M.C., H.Y., S.H.V., K.K.A., J.A.W., R.R.M., P.S., S.B., K.S., E.R., P.B., S.P., C.N., N.E.A., H.B.B., D.T., N.C., M.T.L., F.C., B.L., A.T., F.C.-C., D.T.B., M.T.W.T., M.A.K., S.G., S.P., F.R., C.S., A.A., G.C.-T., S.S., J.G.H., H.D., T.F., P.R., E.G., K.K., S.C.E.B., A.G., Z.X., J.I.S.-V., M.D.G.-P., M.S., G.V., S.P., S.B., R.N.H., J.F.F., D.T.S. and S.J.C. conducted the epidemiologic studies and contributed samples to the bladder cancer GWAS and/or replication. All authors contributed to the writing of the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Montserrat Garcia-Closas (montse.garciaclosas@icr.ac.uk) Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (4M) Supplementary Figures 1–7, Supplementary Tables 1–4 and Supplementary Note Additional data
• A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1
  - Nat Genet 42(11):985-990 (2010)
  Nature Genetics | Letter A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1 * Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 42 ,Pages:985–990Year published:(2010)DOI:doi:10.1038/ng.694Received30 March 2010Accepted31 August 2010Published online17 October 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 × 10−8 and two loci with a combined P < 5 × 10−7). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10−6). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis. View full text Figures at a glance * Figure 1: Plot of genome-wide association results. Genome-wide association results from 523,067 SNPs on chromosomes 1–22 and 12,408 SNPs on the X chromosome using the additive model in SNPTEST. The −log10P values are thresholded at 10−10. Regions in red are described in Table 2. Regions which have been shown previously to be associated with psoriasis and which replicated in this study are highlighted in green, as described in Table 1. * Figure 2: Regional association plots. The −log10P values for the SNPs at eight new loci are shown on the upper part of each plot. SNPs are colored based on their r2 with the labeled hit SNP which has the smallest P value in the region. r2 is calculated from the 58C control data. Where more than one SNP is labeled, there is evidence for multiple signals at the locus (see main text). The bottom section of each plot shows the fine scale recombination rates estimated from individuals in the HapMap population, and genes are marked by horizontal blue lines. Genes within the recombination region of the hit SNPs are labeled, except for 19p13, where the genes are GLP-1, FDX1L, RAVER1, ICAM3, TKY2, CDC37, PDE4A, KEAP1 and S1PR5. * Figure 3: Statistical interaction between ERAP1 and HLA-C genotypes. Odds ratio estimates for ERAP1 genotypes at rs27524 stratified by HLA-C genotypes at rs10484554. Odds ratios were estimated by fitting a logistic regression model that included the first principal component as a covariate and a parameter for each of the possible two-locus genotypes. Note that odds are measured relative to the most protective two-locus genotype (which by definition has an odds ratio of 1). Bars represent 95% CIs calculated from the standard error of the estimates of the genotype parameters in logistic regression model. Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Amy Strange & * Francesca Capon Affiliations * Wellcome Trust Centre for Human Genetics, Oxford, UK. * Amy Strange, * Chris C A Spencer, * Gavin Band, * Céline Bellenguez, * Colin Freeman, * Matti Pirinen, * Anna Rautanen, * Zhan Su & * Peter Donnelly * Division of Genetics and Molecular Medicine, King's College London, London, UK. * Francesca Capon, * Jo Knight, * Michael E Weale, * Michael H Allen, * Christopher G Mathew, * Frank O Nestle, * Alexandros Onoufriadis, * Catherine H Smith, * Jonathan N Barker & * Richard C Trembath * National Institute for Health Research (NIHR), Biomedical Research Centre, Guy's and St. Thomas' National Health Service (NHS) Foundation Trust and King's College London, London, UK. * Jo Knight, * Frank O Nestle & * Richard C Trembath * Arthritis Research, UK Epidemiology Unit, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. * Anne Barton & * Jane Worthington * Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Judith G M Bergboer, * Joost Schalkwijk & * Patrick L J M Zeeuwen * Genetics and Infection Laboratory, Cambridge Institute of Medical Research, Addenbrooke's Hospital, Cambridge, UK. * Jenefer M Blackwell * Division of Psychological Medicine and Psychiatry, Biomedical Research Centre for Mental Health at the Institute of Psychiatry, King's College London and The South London and Maudsley NHS Foundation Trust, Denmark Hill, London, UK. * Elvira Bramon * Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. * Suzannah J Bumpstead, * Panos Deloukas, * Sarah Edkins, * Emma Gray, * Sarah E Hunt, * Cordelia Langford, * Simon C Potter & * Leena Peltonen * Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK. * Juan P Casas * Academic Unit of Dermatology Research, Department of Infection and Immunity, The University of Sheffield, Sheffield, UK. * Michael J Cork & * Rachid Tazi-Ahnini * Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland. * Aiden Corvin * Department of Statistics, University of Oxford, Oxford, UK. * Alexander Dilthey, * Stephen Leslie, * Loukas Moutsianas, * Gilean McVean & * Peter Donnelly * Molecular and Physiological Sciences, The Wellcome Trust, London, UK. * Audrey Duncanson * Genes and Disease Programme, Centre for Genomic Regulation (CRG) and Public Health and Epidemiology Network Biomedical Research Center (CIBERESP), Barcelona, Spain. * Xavier Estivill & * Eva Riveira-Munoz * St. Vincent's University Hospital, Dublin, Ireland. * Oliver Fitzgerald & * Brian Kirby * Department of Biopathology, Centre of Excellence for Genomic risk Assessment in Multifactorial and Complex Diseases, School of Medicine, University of Rome Tor Vergata, Rome, Italy. * Emiliano Giardina & * Giuseppe Novelli * Department of Dermatology, Medical University of Graz, Graz, Austria. * Angelika Hofer, * Wolfgang Salmhofer & * Wolfgang Weger * Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany. * Ulrike Hüffmeier & * André Reis * Department of Clinical Medicine, Trinity College Dublin, Our Lady's Children's Hospital Crumlin, Dublin, Ireland. * Alan D Irvine * Centre for Gastroenterology, Bart's and the London School of Medicine and Dentistry, London, UK. * Janusz Jankowski * Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. * Jesús Lascorz * Department of Dermatology, Western Infirmary, Glasgow, UK. * Joyce Leman & * A David Burden * Dermatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. * Lotus Mallbris, * Mona Ståhle & * Katarina Wolk * Clinical Neurosciences, St. George's University of London, London, UK. * Hugh S Markus * Epithelial Genetics Group, Division of Molecular Medicine, Colleges of Life Sciences and Medicine, Dentistry and Nursing, University of Dundee, Dundee, UK. * W H Irwin McLean * Department of Clinical Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland. * Ross McManus & * Anthony W Ryan * Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland. * Ross McManus & * Anthony W Ryan * Department of Dermatology, University of Göttingen, Göttingen, Germany. * Rotraut Mössner * Department of Medical and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. * Åsa T Naluai & * Lena Samuelsson * Biomedical Research Institute, Ninewells Hospital and Medical School, Dundee, UK. * Colin N A Palmer * La Sapienza University of Rome, Unit of Rheumatology, Department of Clinic and Medical Therapy, Rome, Italy. * Carlo Perricone * Social, Genetic and Developmental Psychiatry Centre, King's College London Institute of Psychiatry, Denmark Hill, London, UK. * Robert Plomin * Dermatology Service, Hospital del Mar-Institut Municipal d'Assisténcia Sanitári (IMAS), Barcelona, Spain. * Ramon M Pujol * University of Cambridge Department of Clinical Neurosciences, Addenbrooke's Hospital, Cambridge, UK. * Stephen J Sawcer & * Adrian Hayday * St. John's Institute of Dermatology, King's College London, London, UK. * Catherine H Smith & * Jonathan N Barker * Department of Dermatology, University of Münster, Münster, Germany. * Heiko Traupe * Glaucoma Research Unit, Moorfields Eye Hospital NHS Foundation Trust, London, UK. * Ananth C Viswanathan * Department of Genetics, University College London Institute of Ophthalmology, London, UK. * Ananth C Viswanathan * Dermatological Sciences, Salford Royal NHS Foundation Trust, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. * Richard B Warren, * Helen S Young & * Christopher E M Griffiths * Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, UK. * Nicholas Wood * Division of Immunology, Infection and Inflammatory Disease, King's College London, London, UK. * Adrian Hayday * Immuno Surveillance Laboratory, London Research Institute, London, UK. * Adrian Hayday * Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden. * Juha Kere * Science for Life Laboratory, Stockholm, Sweden. * Juha Kere * Folkhälsan Institute of Genetics, Helsinki, Finland. * Juha Kere * Department of Medical Genetics, University of Helsinki, Finland. * Juha Kere * Medical Research Council Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Bristol, UK. * David M Evans * Diamantina Institute of Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia. * David M Evans & * Matthew A Brown * These authors jointly supervised this work. * Peter Donnelly & * Richard C Trembath Consortia * Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2 * Amy Strange, * Francesca Capon, * Chris C A Spencer, * Jo Knight, * Michael E Weale, * Michael H Allen, * Anne Barton, * Gavin Band, * Céline Bellenguez, * Judith G M Bergboer, * Jenefer M Blackwell, * Elvira Bramon, * Suzannah J Bumpstead, * Juan P Casas, * Michael J Cork, * Aiden Corvin, * Panos Deloukas, * Alexander Dilthey, * Audrey Duncanson, * Sarah Edkins, * Xavier Estivill, * Oliver Fitzgerald, * Colin Freeman, * Emiliano Giardina, * Emma Gray, * Angelika Hofer, * Ulrike Hüffmeier, * Sarah E Hunt, * Alan D Irvine, * Janusz Jankowski, * Brian Kirby, * Cordelia Langford, * Jesús Lascorz, * Joyce Leman, * Stephen Leslie, * Lotus Mallbris, * Hugh S Markus, * Christopher G Mathew, * W H Irwin McLean, * Ross McManus, * Rotraut Mössner, * Loukas Moutsianas, * Åsa T Naluai, * Frank O Nestle, * Giuseppe Novelli, * Alexandros Onoufriadis, * Colin N A Palmer, * Carlo Perricone, * Matti Pirinen, * Robert Plomin, * Simon C Potter, * Ramon M Pujol, * Anna Rautanen, * Eva Riveira-Munoz, * Anthony W Ryan, * Wolfgang Salmhofer, * Lena Samuelsson, * Stephen J Sawcer, * Joost Schalkwijk, * Catherine H Smith, * Mona Ståhle, * Zhan Su, * Rachid Tazi-Ahnini, * Heiko Traupe, * Ananth C Viswanathan, * Richard B Warren, * Wolfgang Weger, * Katarina Wolk, * Nicholas Wood, * Jane Worthington, * Helen S Young, * Patrick L J M Zeeuwen, * Adrian Hayday, * A David Burden, * Christopher E M Griffiths, * Juha Kere, * André Reis, * Gilean McVean, * David M Evans, * Matthew A Brown, * Jonathan N Barker, * Leena Peltonen, * Peter Donnelly & * Richard C Trembath Contributions F.C., A.D.B., C.E.M.G., J. Kere, A. Reis, J.N.B. and R.C.T. oversaw cohort collection for both the discovery and the replication datasets. The WTCCC2 DNA, genotyping, data quality control and informatics group (S.J.B., P. Deloukas, S.E., E. Gray, S.E.H., C.L. and S.C.P.) executed GWAS sample handling, genotyping and quality control. Members of the WTCCC2 analysis group (C.C.A.S., A.S., G.B., C.B., C.F., M.P., Z.S. and P. Donnelly), J. Knight and M.E.W. performed statistical analyses. A. Dilthey, S.L., L. Moutsianas and G.M. performed HLA imputation and analyses. D.M.E. and M.A.B. provided advice on similarities of association to another autoimmune disease. A.S., F.C., C.C.A.S., J. Knight, M.E.W., A. Hayday, J.N.B., P. Donnelly and R.C.T. contributed to writing the manuscript. The WTCCC2 Management Committee (P. Donnelly (chair), J.M.B., E.B., J.P.C., A. Duncanson, J.J., H.S.M., C.G.M., C.N.A.P., R.P., S.J.S., A. Rautanen, A.C.V., N.W., M.A.B., L.P. and R.C.T.) monitored the ! execution of the GWAS. The GAP Consortium (R.C.T. (chair), M.H.A., A.B., J.G.M.B., M.J.C., A.C., X.E., O.F., E. Giardina, A. Hofer, U.H., A.D.I., B.K., J. Lascorz, J. Leman, L. Mallbris, W.H.I.M., R. McManus, R. Mössner, Å.T.N., F.O.N., G.N., A.O., C.P., R.M.P., E.R.M., A.W.R., W.S., L.S., J.S., C.H.S., M.S., R.T.A., H.T., R.B.W., W.W., K.W., J.W., H.S.Y. and P.L.J.M.Z.) contributed to sample collection. All authors reviewed the final manuscript. The authors of this paper are: Amy Strange1,49, Francesca Capon2,49, Chris C A Spencer1, Jo Knight2,3, Michael E Weale2, Michael H Allen2, Anne Barton4, Gavin Band1, Céline Bellenguez1, Judith G M Bergboer5, Jenefer M Blackwell6, Elvira Bramon7, Suzannah J Bumpstead8, Juan P Casas9, Michael J Cork10, Aiden Corvin11, Panos Deloukas8, Alexander Dilthey12, Audrey Duncanson13, Sarah Edkins8, Xavier Estivill14, Oliver Fitzgerald15, Colin Freeman1, Emiliano Giardina16, Emma Gray8, Angelika Hofer17, Ulrike Hüffmeier18, Sarah E Hunt8, Alan D Irvine19, Janusz Jankowski20, Brian Kirby15, Cordelia Langford8, Jesús Lascorz21, Joyce Leman22, Stephen Leslie12, Lotus Mallbris23, Hugh S Markus24, Christopher G Mathew2, W H Irwin McLean25, Ross McManus26,27, Rotraut Mössner28, Loukas Moutsianas12, Åsa T Naluai29, Frank O Nestle2,3, Giuseppe Novelli16, Alexandros Onoufriadis2, Colin N A Palmer30, Carlo Perricone31, Matti Pirinen1, Robert Plomin32, Simon C Potter8, Ramon M Pujol33, Anna R! autanen1, Eva Riveira-Munoz14, Anthony W Ryan26,27, Wolfgang Salmhofer17, Lena Samuelsson29, Stephen J Sawcer34, Joost Schalkwijk5, Catherine H Smith2,35, Mona Ståhle23, Zhan Su1, Rachid Tazi-Ahnini10, Heiko Traupe36, Ananth C Viswanathan37,38, Richard B Warren39, Wolfgang Weger17, Katarina Wolk23, Nicholas Wood40, Jane Worthington4, Helen S Young39, Patrick L J M Zeeuwen5, Adrian Hayday Zeeuwen34,41,42, A David Burden22, Christopher E M Griffiths39, Juha Kere43,44,45,46, André Reis18, Gilean McVean12, David M Evans47,48, Matthew A Brown48, Jonathan N Barker2,35, Leena Peltonen8, Peter Donnelly1,12,50 & Richard C Trembath2,3,50 Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Peter Donnelly (peter.donnelly@well.ox.ac.uk) or * Richard C Trembath (richard.trembath@kcl.ac.uk) Supplementary information * Author information * Supplementary information Excel files * Supplementary Table 9 (40K) Other SNPs with GWAS p-value less than 10-4 PDF files * Supplementary Text and Figures (7M) Supplementary Tables 1–9, Supplementary Figures 1–4 and Supplementary Note. Additional data
• Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2
  - Nat Genet 42(11):991-995 (2010)
  Nature Genetics | Letter Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2 * Eva Ellinghaus1 Search for this author in: * NPG journals * PubMed * Google Scholar * David Ellinghaus1 Search for this author in: * NPG journals * PubMed * Google Scholar * Philip E Stuart2 Search for this author in: * NPG journals * PubMed * Google Scholar * Rajan P Nair2 Search for this author in: * NPG journals * PubMed * Google Scholar * Sophie Debrus3 Search for this author in: * NPG journals * PubMed * Google Scholar * John V Raelson3 Search for this author in: * NPG journals * PubMed * Google Scholar * Majid Belouchi3 Search for this author in: * NPG journals * PubMed * Google Scholar * Hélène Fournier3 Search for this author in: * NPG journals * PubMed * Google Scholar * Claudia Reinhard3 Search for this author in: * NPG journals * PubMed * Google Scholar * Jun Ding4 Search for this author in: * NPG journals * PubMed * Google Scholar * Yun Li4 Search for this author in: * NPG journals * PubMed * Google Scholar * Trilokraj Tejasvi2 Search for this author in: * NPG journals * PubMed * Google Scholar * Johann Gudjonsson2 Search for this author in: * NPG journals * PubMed * Google Scholar * Stefan W Stoll2 Search for this author in: * NPG journals * PubMed * Google Scholar * John J Voorhees2 Search for this author in: * NPG journals * PubMed * Google Scholar * Sylviane Lambert2 Search for this author in: * NPG journals * PubMed * Google Scholar * Stephan Weidinger5, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Bernadette Eberlein5 Search for this author in: * NPG journals * PubMed * Google Scholar * Manfred Kunz7 Search for this author in: * NPG journals * PubMed * Google Scholar * Proton Rahman8 Search for this author in: * NPG journals * PubMed * Google Scholar * Dafna D Gladman9 Search for this author in: * NPG journals * PubMed * Google Scholar * Christian Gieger10 Search for this author in: * NPG journals * PubMed * Google Scholar * H Erich Wichmann10, 11, 12 Search for this author in: * NPG journals * PubMed * Google Scholar * Tom H Karlsen13 Search for this author in: * NPG journals * PubMed * Google Scholar * Gabriele Mayr14 Search for this author in: * NPG journals * PubMed * Google Scholar * Mario Albrecht14 Search for this author in: * NPG journals * PubMed * Google Scholar * Dieter Kabelitz15 Search for this author in: * NPG journals * PubMed * Google Scholar * Ulrich Mrowietz6 Search for this author in: * NPG journals * PubMed * Google Scholar * Gonçalo R Abecasis4 Search for this author in: * NPG journals * PubMed * Google Scholar * James T Elder2, 16 Search for this author in: * NPG journals * PubMed * Google Scholar * Stefan Schreiber1 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Weichenthal6, 17mweichenthal@dermatology.uni-kiel.de Search for this author in: * NPG journals * PubMed * Google Scholar * Andre Franke1, 17a.franke@mucosa.de Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 42 ,Pages:991–995Year published:(2010)DOI:doi:10.1038/ng.689Received25 February 2010Accepted26 July 2010Published online17 October 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Psoriasis is a multifactorial skin disease characterized by epidermal hyperproliferation and chronic inflammation, the most common form of which is psoriasis vulgaris (PsV). We present a genome-wide association analysis of 2,339,118 SNPs in 472 PsV cases and 1,146 controls from Germany, with follow-up of the 147 most significant SNPs in 2,746 PsV cases and 4,140 controls from three independent replication panels. We identified an association at TRAF3IP2 on 6q21 and genotyped two SNPs at this locus in two additional replication panels (the combined discovery and replication panels consisted of 6,487 cases and 8,037 controls; combined P = 2.36 × 10−10 for rs13210247 and combined P = 1.24 × 10−16 for rs33980500). About 15% of psoriasis cases develop psoriatic arthritis (PsA). A stratified analysis of our datasets including only PsA cases (1,922 cases compared to 8,037 controls, P = 4.57 × 10−12 for rs33980500) suggested that TRAF3IP2 represents a shared susceptibility ! for PsV and PsA. TRAF3IP2 encodes a protein involved in IL-17 signaling and which interacts with members of the Rel/NF-κB transcription factor family. View full text Accession codes * Accession codes * Author information * Supplementary information Referenced accessions GenBank * phs000019.v1.p1 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Michael Weichenthal & * Andre Franke Affiliations * Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany. * Eva Ellinghaus, * David Ellinghaus, * Stefan Schreiber & * Andre Franke * Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA. * Philip E Stuart, * Rajan P Nair, * Trilokraj Tejasvi, * Johann Gudjonsson, * Stefan W Stoll, * John J Voorhees, * Sylviane Lambert & * James T Elder * Genizon BioSciences, Inc., St. Laurent, Quebec, Canada. * Sophie Debrus, * John V Raelson, * Majid Belouchi, * Hélène Fournier & * Claudia Reinhard * Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA. * Jun Ding, * Yun Li & * Gonçalo R Abecasis * Department of Dermatology and Allergy, Technische Universität München, Munich, Germany. * Stephan Weidinger & * Bernadette Eberlein * Department of Dermatology, University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany. * Stephan Weidinger, * Ulrich Mrowietz & * Michael Weichenthal * Comprehensive Center for Inflammation Medicine, University of Lübeck, Lübeck, Germany. * Manfred Kunz * Department of Medicine, Memorial University, St. John's, Newfoundland, Canada. * Proton Rahman * Division of Rheumatology, University of Toronto, Psoriatic Arthritis Program, University Health Network, Toronto, Ontario, Canada. * Dafna D Gladman * Institute of Epidemiology, Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany. * Christian Gieger & * H Erich Wichmann * Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University, Munich, Germany. * H Erich Wichmann * Klinikum Grosshadern, Munich, Germany. * H Erich Wichmann * Clinic for Specialized Medicine and Surgery, Oslo University Hospital Rikshospitalet, Oslo, Norway. * Tom H Karlsen * Max Planck Institute for Informatics, Saarbrücken, Germany. * Gabriele Mayr & * Mario Albrecht * Institute for Immunology, University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany. * Dieter Kabelitz * Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan, USA. * James T Elder Contributions E.E. performed SNP selection, genotyping, data analysis and prepared the figures and tables. A.F. helped with data analysis. D.E. performed imputation, data analysis and generated the regional plots. P.E.S., J.G., J.D. and Y.L. performed the expression and expression quantitative trait loci analyses. S.W.S. and S.L. performed small hairpin RNA (shRNA) experiments. G.R.A. helped with statistical analyses and interpretation of the results. M.A. and G.M. performed in silico protein analyses. M.W., U.M., S.W., B.E. and M.K. coordinated the recruitment and collected phenotype data of panels A and B. C.G. and H.E.W. provided the KORA control samples. J.T.E., J.J.V., R.P.N., T.T., S.D., J.V.R., M.B., H.F., C.R., P.R. and D.D.G. provided the replication samples C through F and the respective genotypes and phenotypes. T.H.K., R.P.N. and D.K. helped with genotyping. E.E. and A.F. drafted the manuscript. D.E., M.W., J.T.E., T.H.K. and S.S. edited the manuscript. A.F. planned and superv! ised the study. All authors approved the final draft. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Andre Franke (a.franke@mucosa.de) or * Michael Weichenthal (mweichenthal@dermatology.uni-kiel.de) Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (3M) Supplementary Figures 1–5 and Supplementary Tables 1–3. Additional data
• Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis
  - Nat Genet 42(11):996-999 (2010)
  Nature Genetics | Letter Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis * Ulrike Hüffmeier1, 18 Search for this author in: * NPG journals * PubMed * Google Scholar * Steffen Uebe1, 18 Search for this author in: * NPG journals * PubMed * Google Scholar * Arif B Ekici1 Search for this author in: * NPG journals * PubMed * Google Scholar * John Bowes2 Search for this author in: * NPG journals * PubMed * Google Scholar * Emiliano Giardina3 Search for this author in: * NPG journals * PubMed * Google Scholar * Eleanor Korendowych4 Search for this author in: * NPG journals * PubMed * Google Scholar * Kristina Juneblad5 Search for this author in: * NPG journals * PubMed * Google Scholar * Maria Apel1 Search for this author in: * NPG journals * PubMed * Google Scholar * Ross McManus6 Search for this author in: * NPG journals * PubMed * Google Scholar * Pauline Ho2 Search for this author in: * NPG journals * PubMed * Google Scholar * Ian N Bruce2 Search for this author in: * NPG journals * PubMed * Google Scholar * Anthony W Ryan6 Search for this author in: * NPG journals * PubMed * Google Scholar * Frank Behrens7 Search for this author in: * NPG journals * PubMed * Google Scholar * Jesús Lascorz1, 17 Search for this author in: * NPG journals * PubMed * Google Scholar * Beate Böhm7 Search for this author in: * NPG journals * PubMed * Google Scholar * Heiko Traupe8 Search for this author in: * NPG journals * PubMed * Google Scholar * Jörg Lohmann9 Search for this author in: * NPG journals * PubMed * Google Scholar * Christian Gieger10 Search for this author in: * NPG journals * PubMed * Google Scholar * Heinz-Erich Wichmann10, 11, 12 Search for this author in: * NPG journals * PubMed * Google Scholar * Christine Herold13 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Steffens13 Search for this author in: * NPG journals * PubMed * Google Scholar * Lars Klareskog14 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas F Wienker13 Search for this author in: * NPG journals * PubMed * Google Scholar * Oliver FitzGerald15 Search for this author in: * NPG journals * PubMed * Google Scholar * Gerd-Marie Alenius5 Search for this author in: * NPG journals * PubMed * Google Scholar * Neil J McHugh4, 16 Search for this author in: * NPG journals * PubMed * Google Scholar * Giuseppe Novelli3 Search for this author in: * NPG journals * PubMed * Google Scholar * Harald Burkhardt7, 19 Search for this author in: * NPG journals * PubMed * Google Scholar * Anne Barton2, 19 Search for this author in: * NPG journals * PubMed * Google Scholar * André Reis1, 19andre.reis@uk-erlangen.de Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 42 ,Pages:996–999Year published:(2010)DOI:doi:10.1038/ng.688Received25 January 2010Accepted13 September 2010Published online17 October 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10−17). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10−3). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10−20, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as ! a new and shared pathway for PsA and PsV. View full text Figures at a glance * Figure 1: Genome wide association results from the initial GWAS analysis. Negative decadic logarithms of genomic control corrected EIGENSTRAT P values are plotted against genomic position (hg18). () Plot of 1,585,307 SNPs (after imputation) in 572 German psoriatic arthritis cases versus 888 German controls. The red line represents the genome wide significance threshold of 5 × 10−8. () Regional association of the TRAF3IP2 region. Genotyped SNPs appear in red and imputed SNPs appear in blue. The recombination rate (from HapMap data) is indicated by the light blue graph. * Figure 2: Haplotype and functional analysis of associated variants in TRAF3IP2. () The exon and intron structure of TRAF3IP2 with the location of associated SNPs. The four most common haplotypes in a combined set of 2,077 PsA cases and 2,648 control individuals of European origin and their frequency within cases are given. Risk alleles are in bold type. For each haplotype, odds ratios and 95% CIs (in brackets) compare the occurrence of this haplotype compared to all three other haplotypes. () Interaction of wildtype TRAF3IP2 (ACT1) and the PsA-associated variants p.Asp10Asn and p.Arg74Trp with TRAF6 in a mammalian two-hybrid dual-luciferase reporter assay. Depicted are means of relative normalized luminescence units reflecting the specific induction of firefly luciferase by the interaction of the cotransfected ligand pairs TRAF3IP2 and TRAF6 (blue bars). The investigated TRAF3IP2 variants include constructs harboring one of the single missense variants (p.Asp10Asn or p.Arg74Trp) or both. To exclude autoactivation activity, each prey and bait construct w! as separately cotransfected with reporter plasmids into HEK293 cells in the absence of any potential interaction partner (open bars). P53 and TRAF2 as a pair of non-interacting proteins served as an additional independent negative control. Error bars represent 95% CIs. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions GenBank * NM_147686 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Ulrike Hüffmeier & * Steffen Uebe Affiliations * Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany. * Ulrike Hüffmeier, * Steffen Uebe, * Arif B Ekici, * Maria Apel, * Jesús Lascorz & * André Reis * Arthritis Research UK Epidemiology Unit, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK. * John Bowes, * Pauline Ho, * Ian N Bruce & * Anne Barton * Department of Biopathology, Centre of Excellence for Genomic Risk Assessment in Multifactorial and Complex Diseases, School of Medicine, University of Rome 'Tor Vergata' and Fondazione PTV 'Policlinico Tor Vergata', Rome, Italy. * Emiliano Giardina & * Giuseppe Novelli * Royal National Hospital for Rheumatic Diseases, Bath, UK. * Eleanor Korendowych & * Neil J McHugh * Department of Public Health and Clinical Medicine, Rheumatology, University Hospital, Umeå, Sweden. * Kristina Juneblad & * Gerd-Marie Alenius * Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland. * Ross McManus & * Anthony W Ryan * Division of Rheumatology, Department of Internal Medicine II, Johann Wolfgang Goethe University, Frankfurt am Main, Germany. * Frank Behrens, * Beate Böhm & * Harald Burkhardt * Department of Dermatology, University of Münster, Münster, Germany. * Heiko Traupe * Psoriasis Rehabilitation Hospital, Bad Bentheim, Germany. * Jörg Lohmann * Institute of Epidemiology, Helmholtz Center Munich, Munich, Germany. * Christian Gieger & * Heinz-Erich Wichmann * Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany. * Heinz-Erich Wichmann * Klinikum Grosshadern, Munich, Germany. * Heinz-Erich Wichmann * Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany. * Christine Herold, * Michael Steffens & * Thomas F Wienker * Karolinska Institute, Stockholm, Sweden. * Lars Klareskog * Department of Rheumatology, St. Vincent's University Hospital, University College Dublin (UCD) School of Medicine and Medical Science and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland. * Oliver FitzGerald * Department of Pharmacy and Pharmacology, University of Bath, Bath, UK. * Neil J McHugh * Present address: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. * Jesús Lascorz * These authors jointly supervised this work. * Harald Burkhardt, * Anne Barton & * André Reis Contributions H.B., A.B. and A.R. designed the study and worked out its concept. U.H., A.B.E., M.A. and J.B. planned and performed genotyping with genome-wide arrays and/or assays for single SNPs, and U.H., S.U., A.B.E., J.B., M.A., C.H., M.S., T.F.W. and A.R. analyzed genetic data. B.B. and H.B. performed functional studies. U.H., J.B., E.G., E.K., K.J., R.M., P.H., I.N.B., A.W.R., F.B., J. Lascorz, H.T., J. Lohmann, C.G., H.-E.W., O.F., G.-M.A., N.J.M., G.N., H.B. and A.B. recruited subjects and control individuals and collected the phenotypic data. U.H., S.U., H.B. and A.R. wrote a first draft of the manuscript. A.B. edited the manuscript in a major way. All authors reviewed and approved the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * André Reis (andre.reis@uk-erlangen.de) Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (820K) Supplementary Figures 1–3, Supplementary Tables 1–4 and Supplementary Note. Additional data
• Genome-wide association analysis identifies three psoriasis susceptibility loci
  - Nat Genet 42(11):1000-1004 (2010)
  Nature Genetics | Letter Genome-wide association analysis identifies three psoriasis susceptibility loci * Philip E Stuart1, 15 Search for this author in: * NPG journals * PubMed * Google Scholar * Rajan P Nair1, 15 Search for this author in: * NPG journals * PubMed * Google Scholar * Eva Ellinghaus2 Search for this author in: * NPG journals * PubMed * Google Scholar * Jun Ding3 Search for this author in: * NPG journals * PubMed * Google Scholar * Trilokraj Tejasvi1 Search for this author in: * NPG journals * PubMed * Google Scholar * Johann E Gudjonsson1 Search for this author in: * NPG journals * PubMed * Google Scholar * Yun Li3 Search for this author in: * NPG journals * PubMed * Google Scholar * Stephan Weidinger4 Search for this author in: * NPG journals * PubMed * Google Scholar * Bernadette Eberlein4 Search for this author in: * NPG journals * PubMed * Google Scholar * Christian Gieger5 Search for this author in: * NPG journals * PubMed * Google Scholar * H Erich Wichmann5 Search for this author in: * NPG journals * PubMed * Google Scholar * Manfred Kunz6 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert Ike7 Search for this author in: * NPG journals * PubMed * Google Scholar * Gerald G Krueger8 Search for this author in: * NPG journals * PubMed * Google Scholar * Anne M Bowcock9 Search for this author in: * NPG journals * PubMed * Google Scholar * Ulrich Mrowietz10 Search for this author in: * NPG journals * PubMed * Google Scholar * Henry W Lim11 Search for this author in: * NPG journals * PubMed * Google Scholar * John J Voorhees1 Search for this author in: * NPG journals * PubMed * Google Scholar * Gonçalo R Abecasis3 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Weichenthal10 Search for this author in: * NPG journals * PubMed * Google Scholar * Andre Franke2 Search for this author in: * NPG journals * PubMed * Google Scholar * Proton Rahman12 Search for this author in: * NPG journals * PubMed * Google Scholar * Dafna D Gladman13 Search for this author in: * NPG journals * PubMed * Google Scholar * James T Elder1, 14jelder@umich.edu Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 42 ,Pages:1000–1004Year published:(2010)DOI:doi:10.1038/ng.693Received09 March 2010Accepted09 July 2010Published online17 October 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg We carried out a meta-analysis of two recent psoriasis genome-wide association studies1, 2 with a combined discovery sample of 1,831 affected individuals (cases) and 2,546 controls. One hundred and two loci selected based on P value rankings were followed up in a three-stage replication study including 4,064 cases and 4,685 controls from Michigan, Toronto, Newfoundland and Germany. In the combined meta-analysis, we identified three new susceptibility loci, including one at NOS2 (rs4795067, combined P = 4 × 10−11), one at FBXL19 (rs10782001, combined P = 9 × 10−10) and one near PSMA6-NFKBIA (rs12586317, combined P = 2 × 10−8). All three loci were also associated with psoriatic arthritis (rs4795067, combined P = 1 × 10−5; rs10782001, combined P = 4 × 10−8; and rs12586317, combined P = 6 × 10−5) and purely cutaneous psoriasis (rs4795067, combined P = 1 × 10−8; rs10782001, combined P = 2 × 10−6; and rs12586317, combined P = 1 × 10−6). We also replicate! d a recently identified3 association signal near RNF114 (rs495337, combined P = 2 × 10−7). View full text Figures at a glance * Figure 1: Evidence for psoriasis association in four genomic regions including the three new loci attaining genome-wide significance and the confirmed RNF114 region. The upper portion of each plot depicts association P values for a meta-analysis of the CASP and Kiel discovery GWAS using 1000 Genomes Project–based imputation and the lower portion depicts RefSeq genes and LD plots from the phase 2 HapMap CEU sample. For each region, the most strongly associated replicated SNP is highlighted in red, as are its P values for the discovery, replication and combined samples. * Figure 2: Expression data for notable candidate genes within the three psoriasis-associated regions. Log2-transformed levels of mRNA assayed by qRT-PCR are shown for normal (NN), uninvolved (PN) and lesional psoriatic (PP) skin. Figures include both individual measurements (jittered scatterplots) and box plots summarizing the distribution. Bars and significance levels are shown for all pairwise comparisons of mean mRNA levels that are significant at a nominal (P ≤ 0.05) level. Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Philip E Stuart & * Rajan P Nair Affiliations * Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA. * Philip E Stuart, * Rajan P Nair, * Trilokraj Tejasvi, * Johann E Gudjonsson, * John J Voorhees & * James T Elder * Institute for Clinical Molecular Biology, University of Kiel, Kiel, Germany. * Eva Ellinghaus & * Andre Franke * Center for Statistical Genetics, Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA. * Jun Ding, * Yun Li & * Gonçalo R Abecasis * Department of Dermatology and Allergy, Technical University Munich, Munich, Germany. * Stephan Weidinger & * Bernadette Eberlein * Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University, Munich, Germany. * Christian Gieger & * H Erich Wichmann * Comprehensive Center for Inflammation Medicine, University of Lübeck, Lübeck, Germany. * Manfred Kunz * Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA. * Robert Ike * Department of Dermatology, University of Utah, Salt Lake City, Utah, USA. * Gerald G Krueger * Division of Human Genetics, Department of Genetics, Washington University at St. Louis, St. Louis, Missouri, USA. * Anne M Bowcock * Department of Dermatology, University of Kiel, Kiel, Germany. * Ulrich Mrowietz & * Michael Weichenthal * Department of Dermatology, Henry Ford Hospital, Detroit, Michigan, USA. * Henry W Lim * Department of Medicine, Memorial University, St. John's, Newfoundland, Canada. * Proton Rahman * Department of Rheumatology, University of Toronto, Toronto, Ontario, Canada. * Dafna D Gladman * Ann Arbor Veterans Affairs Medical Center, Ann Arbor, Michigan, USA. * James T Elder Contributions R.P.N., P.E.S. and J.T.E. performed SNP selection, data analysis and prepared the figures and tables. R.P.N., T.T., P.E.S., P.R. and E.E. performed genotyping. P.E.S., Y.L. and J.D. performed genotype imputation and association analyses, and P.E.S., J.E.G., and J.D. performed the expression analyses. G.R.A. helped with statistical analyses and interpretation of results. R.P.N., T.T., J.J.V., R.I., M.W., S.W., B.E., C.G., H.E.W., H.W.L., P.R., M.K., U.M. and D.D.G. coordinated subject recruitment and collected phenotype data. J.T.E., G.G.K. and A.M.B. contributed genotypes and phenotypes from the CASP discovery GWAS. J.T.E. and P.E.S. drafted the manuscript; R.P.N., G.R.A., E.E., M.W. and A.F. edited the manuscript; and J.T.E. planned and supervised the study. All authors approved the final draft. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * James T Elder (jelder@umich.edu) Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (3M) Supplementary Tables 1–6 and Supplementary Figures 1 and 2. Additional data
• Association analyses identify six new psoriasis susceptibility loci in the Chinese population
  - Nat Genet 42(11):1005-1009 (2010)
  Nature Genetics | Letter Association analyses identify six new psoriasis susceptibility loci in the Chinese population * Liang-Dan Sun1, 2, 3, 18 Search for this author in: * NPG journals * PubMed * Google Scholar * Hui Cheng1, 2, 3, 18 Search for this author in: * NPG journals * PubMed * Google Scholar * Zai-Xing Wang1, 2, 3, 18 Search for this author in: * NPG journals * PubMed * Google Scholar * An-Ping Zhang1, 2, 3, 18 Search for this author in: * NPG journals * PubMed * Google Scholar * Pei-Guang Wang1, 2, 3, 18 Search for this author in: * NPG journals * PubMed * Google Scholar * Jin-Hua Xu4 Search for this author in: * NPG journals * PubMed * Google Scholar * Qi-Xing Zhu1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Hai-Sheng Zhou3, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Eva Ellinghaus6 Search for this author in: * NPG journals * PubMed * Google Scholar * Fu-Ren Zhang2, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Xiong-Ming Pu2, 8 Search for this author in: * NPG journals * PubMed * Google Scholar * Xue-Qin Yang2, 9 Search for this author in: * NPG journals * PubMed * Google Scholar * Jian-Zhong Zhang10 Search for this author in: * NPG journals * PubMed * Google Scholar * Ai-E Xu2, 11 Search for this author in: * NPG journals * PubMed * Google Scholar * Ri-Na Wu12 Search for this author in: * NPG journals * PubMed * Google Scholar * Li-Min Xu13 Search for this author in: * NPG journals * PubMed * Google Scholar * Lin Peng14 Search for this author in: * NPG journals * PubMed * Google Scholar * Cynthia A Helms14 Search for this author in: * NPG journals * PubMed * Google Scholar * Yun-Qing Ren1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Chi Zhang1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Shu-Mei Zhang1, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Rajan P Nair15 Search for this author in: * NPG journals * PubMed * Google Scholar * Hong-Yan Wang1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Guo-Shu Lin1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Philip E Stuart15 Search for this author in: * NPG journals * PubMed * Google Scholar * Xing Fan1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Gang Chen2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Trilokraj Tejasvi15 Search for this author in: * NPG journals * PubMed * Google Scholar * Pan Li1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Jun Zhu1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Zhi-Ming Li1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Hong-Mei Ge1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Weichenthal16 Search for this author in: * NPG journals * PubMed * Google Scholar * Wen-Zheng Ye1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Cheng Zhang1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Song-Ke Shen1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Bao-Qi Yang7 Search for this author in: * NPG journals * PubMed * Google Scholar * Yuan-Yuan Sun1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Shan-Shan Li1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Yan Lin1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Jian-Hua Jiang8 Search for this author in: * NPG journals * PubMed * Google Scholar * Cun-Tao Li1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Ri-Xin Chen1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Juan Cheng9 Search for this author in: * NPG journals * PubMed * Google Scholar * Xin Jiang1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Peng Zhang1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Wei-Min Song11 Search for this author in: * NPG journals * PubMed * Google Scholar * Jin Tang1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Hao-Qin Zhang1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Li Sun12 Search for this author in: * NPG journals * PubMed * Google Scholar * Jing Cui1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Li-Jun Zhang1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Biao Tang1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Fei Huang1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Qian Qin1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Xiao-Ping Pei1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Ai-Min Zhou13 Search for this author in: * NPG journals * PubMed * Google Scholar * Li-Mei Shao1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Jian-Lan Liu1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Feng-Yu Zhang1, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Wei-Dong Du1, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Andre Franke6 Search for this author in: * NPG journals * PubMed * Google Scholar * Anne M Bowcock14 Search for this author in: * NPG journals * PubMed * Google Scholar * James T Elder15 Search for this author in: * NPG journals * PubMed * Google Scholar * Jian-Jun Liu1, 3, 17 Search for this author in: * NPG journals * PubMed * Google Scholar * Sen Yang1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Xue-Jun Zhang1, 2, 3, 4ayzxj@vip.sina.com Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 42 ,Pages:1005–1009Year published:(2010)DOI:doi:10.1038/ng.690Received08 February 2010Accepted20 July 2010Published online17 October 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg We extended our previous genome-wide association study for psoriasis with a multistage replication study including 8,312 individuals with psoriasis (cases) and 12,919 controls from China as well as 3,293 cases and 4,188 controls from Germany and the United States and 254 nuclear families from the United States. We identified six new susceptibility loci associated with psoriasis in the Chinese study containing the candidate genes ERAP1, PTTG1, CSMD1, GJB2, SERPINB8 and ZNF816A (combined P < 5 × 10−8) and replicated one locus, 5q33.1 (TNIP1-ANXA6), previously reported (combined P = 3.8 × 10−21) in the European studies. Two of these loci showed evidence for association in the German study at ZNF816A and GJB2 with P = 3.6 × 10−3 and P = 7.9 × 10−3, respectively. ERAP1 and ZNF816A were associated with type 1 (early onset) psoriasis in the Chinese Han population (test for heterogeneity P = 6.5 × 10−3 and P = 1.5 × 10−3, respectively). Comparisons with the results! of previous GWAS of psoriasis highlight the heterogeneity of disease susceptibility between the Chinese and European populations. Our study identifies new genetic susceptibility factors and suggests new biological pathways in psoriasis. View full text Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Liang-Dan Sun, * Hui Cheng, * Zai-Xing Wang, * An-Ping Zhang & * Pei-Guang Wang Affiliations * Institute of Dermatology and Department of Dermatology at No.1 Hospital, Anhui Medical University, Hefei, Anhui, China. * Liang-Dan Sun, * Hui Cheng, * Zai-Xing Wang, * An-Ping Zhang, * Pei-Guang Wang, * Qi-Xing Zhu, * Yun-Qing Ren, * Chi Zhang, * Shu-Mei Zhang, * Hong-Yan Wang, * Guo-Shu Lin, * Xing Fan, * Pan Li, * Jun Zhu, * Zhi-Ming Li, * Hong-Mei Ge, * Wen-Zheng Ye, * Cheng Zhang, * Song-Ke Shen, * Yuan-Yuan Sun, * Shan-Shan Li, * Yan Lin, * Cun-Tao Li, * Ri-Xin Chen, * Xin Jiang, * Peng Zhang, * Jin Tang, * Hao-Qin Zhang, * Jing Cui, * Li-Jun Zhang, * Biao Tang, * Fei Huang, * Qian Qin, * Xiao-Ping Pei, * Li-Mei Shao, * Jian-Lan Liu, * Feng-Yu Zhang, * Wei-Dong Du, * Jian-Jun Liu, * Sen Yang & * Xue-Jun Zhang * Department of Dermatology and Venereology, Anhui Medical University, Hefei, Anhui, China. * Liang-Dan Sun, * Hui Cheng, * Zai-Xing Wang, * An-Ping Zhang, * Pei-Guang Wang, * Qi-Xing Zhu, * Fu-Ren Zhang, * Xiong-Ming Pu, * Xue-Qin Yang, * Ai-E Xu, * Yun-Qing Ren, * Chi Zhang, * Hong-Yan Wang, * Guo-Shu Lin, * Xing Fan, * Gang Chen, * Pan Li, * Jun Zhu, * Zhi-Ming Li, * Hong-Mei Ge, * Wen-Zheng Ye, * Cheng Zhang, * Song-Ke Shen, * Yuan-Yuan Sun, * Shan-Shan Li, * Yan Lin, * Cun-Tao Li, * Ri-Xin Chen, * Xin Jiang, * Peng Zhang, * Jin Tang, * Hao-Qin Zhang, * Jing Cui, * Li-Jun Zhang, * Biao Tang, * Fei Huang, * Qian Qin, * Xiao-Ping Pei, * Li-Mei Shao, * Jian-Lan Liu, * Sen Yang & * Xue-Jun Zhang * State Key Laboratory Incubation Base of Dermatology, Ministry of National Science and Technology, Hefei, Anhui, China. * Liang-Dan Sun, * Hui Cheng, * Zai-Xing Wang, * An-Ping Zhang, * Pei-Guang Wang, * Qi-Xing Zhu, * Hai-Sheng Zhou, * Yun-Qing Ren, * Chi Zhang, * Shu-Mei Zhang, * Hong-Yan Wang, * Guo-Shu Lin, * Xing Fan, * Gang Chen, * Pan Li, * Jun Zhu, * Zhi-Ming Li, * Hong-Mei Ge, * Wen-Zheng Ye, * Cheng Zhang, * Song-Ke Shen, * Yuan-Yuan Sun, * Shan-Shan Li, * Yan Lin, * Cun-Tao Li, * Ri-Xin Chen, * Xin Jiang, * Peng Zhang, * Jin Tang, * Hao-Qin Zhang, * Jing Cui, * Li-Jun Zhang, * Biao Tang, * Fei Huang, * Qian Qin, * Xiao-Ping Pei, * Li-Mei Shao, * Jian-Lan Liu, * Feng-Yu Zhang, * Wei-Dong Du, * Jian-Jun Liu, * Sen Yang & * Xue-Jun Zhang * Department of Dermatology, Huashan Hospital of Fudan University, Shanghai, China. * Jin-Hua Xu & * Xue-Jun Zhang * Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei, Anhui, China. * Hai-Sheng Zhou * Institute of Clinical Molecular Biology, Christian-Albrechts University, Kiel, Germany. * Eva Ellinghaus & * Andre Franke * Shandong Provincial Institute of Dermatology and Venereology, Jinan, Shandong, China. * Fu-Ren Zhang & * Bao-Qi Yang * Department of Dermatology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumchi, Xinjiang, China. * Xiong-Ming Pu & * Jian-Hua Jiang * Department of Dermatology, The General Hospital of Air Force, People's Liberation Army (PLA), Beijing, China. * Xue-Qin Yang & * Juan Cheng * Department of Dermatology, Peking University People's Hospital, Beijing, China. * Jian-Zhong Zhang * The Third People's Hospital of Hangzhou, Hangzhou, Zhejiang, China. * Ai-E Xu & * Wei-Min Song * Department of Dermatology, The Affiliated Hospital of Inner Mongolia Medical College, Huhehot, Inner Mongolia, China. * Ri-Na Wu & * Li Sun * Department of Dermatology, Changzheng Hospital, Tianjin, China. * Li-Min Xu & * Ai-Min Zhou * Division of Human Genetics, Washington University School of Medicine, St. Louis, Missouri, USA. * Lin Peng, * Cynthia A Helms & * Anne M Bowcock * Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA. * Rajan P Nair, * Philip E Stuart, * Trilokraj Tejasvi & * James T Elder * Department of Dermatology, University Hospital of Schleswig-Holstein, Kiel, Germany. * Michael Weichenthal * Human Genetics, Genome Institute of Singapore, Singapore, Singapore. * Jian-Jun Liu Contributions X.-J.Z. conceived of this study and obtained financial support. X.-J.Z., S.Y. and L.-D.S. designed the study. H.C., Z.-X.W., A.-P.Z. and P.-G.W. participated in the study design and were responsible for sample selection, genotyping and project management. J.T.E., A.F., A.M.B., J.-H.X., Q.-X.Z., F.-R.Z., X.-M.P., X.-Q.Y., J.-Z.Z., A.-E.X., R.-N.W., L.-M.X., M.W., G.-S.L., Z.-M.L., H.-M.G., W.-Z.Y., Cheng Zhang, B.-Q.Y., Y.-Y.S., S.-S.L., Y.L., J.-H.J., C.-T.L., R.-X.C., X.J., P.Z., W.-M.S., J.T., H.-Q.Z., L.S., J. Cui, J. Cheng, L.-J.Z., B.T., F.H., Q.Q., X.-P.P., A.-M.Z., L.-M.S. and J.-L.L. conducted sample selection and data management, undertook recruitment, collected phenotype data, undertook related data handling and calculation, managed recruitment and obtained biological samples. S.-M.Z., H.-Y.W., X.F., G.C., P.L., J.Z., H.-S.Z., T.T. and S.-K.S. performed genotyping analysis. Y.-Q.R., Chi Zhang, R.P.N., P.E.S., E.E., J.-J.L., F.-Y.Z. and W.-D.D. undertook data proces! sing, statistical analysis and bioinformatics investigations. C.A.H. performed analyses and designed genotyping assays for the 254 nuclear families, which was performed by L.P. and A.M.B. All the authors contributed to the final paper, with X.-J.Z., S.Y., L.-D.S., H.C., Z.-X.W., J.T.E., P.E.S., A.M.B., A.F., A.-P.Z. and P.-G.W. playing key roles. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Xue-Jun Zhang (ayzxj@vip.sina.com) Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (652K) Supplementary Figures 1 and 2 and Supplementary Tables 1–6. Additional data
• WDR62 is associated with the spindle pole and is mutated in human microcephaly
  - Nat Genet 42(11):1010-1014 (2010)
  Nature Genetics | Letter WDR62 is associated with the spindle pole and is mutated in human microcephaly * Adeline K Nicholas1, 11 Search for this author in: * NPG journals * PubMed * Google Scholar * Maryam Khurshid1, 11 Search for this author in: * NPG journals * PubMed * Google Scholar * Julie Désir2, 11 Search for this author in: * NPG journals * PubMed * Google Scholar * Ofélia P Carvalho1 Search for this author in: * NPG journals * PubMed * Google Scholar * James J Cox1 Search for this author in: * NPG journals * PubMed * Google Scholar * Gemma Thornton1 Search for this author in: * NPG journals * PubMed * Google Scholar * Rizwana Kausar3 Search for this author in: * NPG journals * PubMed * Google Scholar * Muhammad Ansar3 Search for this author in: * NPG journals * PubMed * Google Scholar * Wasim Ahmad3 Search for this author in: * NPG journals * PubMed * Google Scholar * Alain Verloes4 Search for this author in: * NPG journals * PubMed * Google Scholar * Sandrine Passemard4, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Jean-Paul Misson6 Search for this author in: * NPG journals * PubMed * Google Scholar * Susan Lindsay7 Search for this author in: * NPG journals * PubMed * Google Scholar * Fanni Gergely8 Search for this author in: * NPG journals * PubMed * Google Scholar * William B Dobyns9 Search for this author in: * NPG journals * PubMed * Google Scholar * Emma Roberts10 Search for this author in: * NPG journals * PubMed * Google Scholar * Marc Abramowicz2marcabra@ulb.ac.be Search for this author in: * NPG journals * PubMed * Google Scholar * C Geoffrey Woods1cw347@cam.ac.uk Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 42 ,Pages:1010–1014Year published:(2010)DOI:doi:10.1038/ng.682Received27 May 2010Accepted10 September 2010Published online03 October 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Autosomal recessive primary microcephaly (MCPH) is a disorder of neurodevelopment resulting in a small brain1, 2. We identified WDR62 as the second most common cause of MCPH after finding homozygous missense and frame-shifting mutations in seven MCPH families. In human cell lines, we found that WDR62 is a spindle pole protein, as are ASPM and STIL, the MCPH7 and MCHP7 proteins3, 4, 5. Mutant WDR62 proteins failed to localize to the mitotic spindle pole. In human and mouse embryonic brain, we found that WDR62 expression was restricted to neural precursors undergoing mitosis. These data lend support to the hypothesis that the exquisite control of the cleavage furrow orientation in mammalian neural precursor cell mitosis, controlled in great part by the centrosomes and spindle poles, is critical both in causing MCPH when perturbed and, when modulated, generating the evolutionarily enlarged human brain6, 7, 8, 9. View full text Figures at a glance * Figure 1: A summary of the linkage strategy used to define the MCPH2 region and mutations found in WDR62 in MCPH2 families. () From left to right, chromosome 19, shown as a G-banded cartoon; the initial linkage region defined by homozygous microsatellite markers; the final minimal linkage region defined by homozygous SNPs; the region subject to genome capture (slightly larger and overlapping the minimal linkage region); and WDR62 shown as an arrow pointing from 5′ to 3′. Critical defining heterozygous markers are shown that bound each defined region. () WDR62 is shown from 5′ to 3′, from left to right. Exons are shown to scale and introns are shown as an artificial fixed interval for clarity. The position of each homozygous mutation is shown. The lengths of the gene and protein are given. Below the gene, the WDR62 protein is shown with each WD repeat detected by PFAM, shown as a filled in triangle. The position that each DNA mutation affects the WDR62 protein is shown beneath, with indication of the resultant amino acid or peptide change. For the c.4241dupT mutation (resulting in the p.Le! u1414LeufsX41 alteration), an explanatory cartoon is shown at the bottom of the figure. This mutation causes a frame shift in the penultimate exon of WDR62, which does not give rise to a new stop codon until the terminal exon. After the frame shift, 17 novel amino acids were found, and those amino acids at the start of the frame shift, at the splice sites and at the position of the new premature stop codon are shown. * Figure 2: Subcellular localization of WDR62 throughout the cell cycle. Confocal microscopy analysis of HeLa cells during each stage of the cell cycle. WDR62 staining is weak and cytoplasmic during interphase, with a concentration at a perinuclear position suggestive of the Golgi apparatus, and shows spindle pole localization during mitosis. Cells were stained with antibodies against human WDR62 (red), γ-tubulin (green) as a centrosome marker, α-tubulin (white) as a microtubule marker, and DNA (blue) stained with DAPI. Scale bar, 5 μm. * Figure 3: Overexpression of WDR62-GFP wild type and c.1313G>A (p.Arg438His) mutant constructs in HeLa cells. The first 4 × 5 panel of images (on the left) shows the results for the wild-type WDR62-GFP construct, whereas the second 4 × 5 panel of images (on the right) shows the comparable results for the c.1313G>A (p.Arg438His) missense mutation in the WDR62-GFP construct. The wild-type WDR62-GFP protein localized to the spindle pole during mitosis (in 50 of 50 cells analyzed), paralleling the localization found for the endogenous wild type protein. Conversely, in cells expressing the mutant construct, there was no spindle pole accumulation of GFP during mitosis (in 50 of 50 cells analyzed). Cells were stained with γ-tubulin (red) as a centrosome marker and α-tubulin (white) identifying microtubules and the mitotic spindle. Both WDR62-GFP (green) proteins were directly visualized with DNA (blue) stained with DAPI. (See Supplementary Fig. 4 for the results for the c.4241dupT mutation). Scale bar, 5 μm. * Figure 4: Endogenous expression pattern of WDR62 in human and mouse embryonic brain. () Wdr62 expression in mouse cerebral cortex neuroepithelium from early to late neurogenesis: E11, E13 and E15. Wdr62 is seen to concentrate in the cytoplasm of mitotic apical and basal neural precursor cells. In the cortical plate containing newly born neurons, seen after E13, Wdr62 is also found in the nucleus of newly born neurons. () A magnified image of mouse E13 neuroepithelium clearly showing Wdr62 cytoplasmic aggregation in apical mitotic precursors. The arrows indicate examples of apical neural precursor cells undergoing mitosis with a pair of centrosomes on either side of a metaphase DNA plate. In the neuroepithelium, Wdr62 expression is only clearly seen in cells undergoing mitosis. () A magnified image of human CS22 cerebral cortex neuroepithelium showing WDR62 cytoplasmic aggregation in apical mitotic precursors. Arrows indicate cells in which WDR62 expression can be most clearly seen, which by their position and nuclear morphology are likely to be undergoing mi! tosis. Due to collection, fixation and subsequent paraffin embedding, immunohistochemistry is more difficult in human embryonic brain sections; however, the apically positioned centrosomes of the apical neural precursors are clearly visible. For each set of images, the result are shown for WDR62 and Wdr62 (red), with γ-tubulin (white) as a centrosome marker, Nestin (green) marking apical neural precursors in the cytoplasm and DNA (blue) stained with DAPI. Scale bars, 10 μm. * Figure 5: Wdr62 expression in newborn, newly arrived cortical neurons in the developing cerebral cortex and brain imaging from two individuals with WDR62 mutations. () Newborn neuron data. Mouse cerebral cortex neuroepithelium in early and later neurogenesis stages E11 and E13 stained with antibodies to Wdr62 (red) and costained against the neuronal marker protein Tubulinβ3 (white) with DNA (blue) stained with DAPI. The apical ventricular margin of the neuroepithelium is shown on the left of each image; on the right of each image is the outer, pial surface of the developing cerebral cortex. The developing cerebral cortex is bounded by Tubulinβ3 staining to the right of each image. Localization of Wdr62 to the developing cortical plate can be seen at the right of each image. An outermost Wdr62 staining is also seen, beyond the cerebral cortex, which represents staining of pial membrane cells. Scale bars, 10 μm. () An enlargement of an E13 merged image allowing easier visualization of neurons staining with Tubulinβ3 (white). The single arrows indicate neurons in which Wdr62 staining is nuclear. Also visible are cells, indicated by dou! ble arrows, undergoing mitosis in the subventricular zones with prominent Wdr62 staining in the cytoplasm, which are assumed to be basal or intermediate neural progenitors. () MRI images of individuals with MCPH2 from this study with homozygous WDR62 mutations; the c.1313G>A missense mutation is shown above and the protein truncating c.3936dupC mutation is shown below. The annotation in red indicates: 1, cortex normal thickness (3–4 mm) but having an indistinct border; 2, diffuse simplified gyral pattern with frontal cortex most severely affected (this feature is more marked for the null mutation); and 3, cortex appears mildly thickened (~5 mm). Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Adeline K Nicholas, * Maryam Khurshid & * Julie Désir Affiliations * Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK. * Adeline K Nicholas, * Maryam Khurshid, * Ofélia P Carvalho, * James J Cox, * Gemma Thornton & * C Geoffrey Woods * Department of Medical Genetics, Hôpital Erasme and Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université libre de Bruxelles (IRIBHM), ULB, Brussels, Belgium. * Julie Désir & * Marc Abramowicz * Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan. * Rizwana Kausar, * Muhammad Ansar & * Wasim Ahmad * Department of Genetics, Robert Debré University Hospital, Paris, France. * Alain Verloes & * Sandrine Passemard * Department of Child Neurology, Assistance publique-Hôpitaux de Paris (AP-HP) Robert Debré University Hospital, Paris, France. * Sandrine Passemard * University of Liège Medical School and Department of Pediatrics, La Citadelle University Hospital, Liège, Belgium. * Jean-Paul Misson * Institute of Human Genetics, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK. * Susan Lindsay * Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK. * Fanni Gergely * University of Chicago, Department of Human Genetics, Chicago, Illinois, USA. * William B Dobyns * Microcephaly and Neurogenesis research group, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, UK. * Emma Roberts Contributions The following authors contributed to the design of the study: A.K.N., M.K., J.J.C., F.G., E.R., M. Abramowicz and C.G.W. The following authors generated experimental data: A.K.N., M.K., J.D., O.P.C., G.T., R.K., M. Ansar, F.G., W.B.D., E.R. and C.G.W. Reagents were contributed by R.K., M. Abramowicz, W.A., A.L., S.P., J.-P.M., S.L., M. Abramowicz and C.G.W. The paper was written by A.K.N., M.K., O.P.C., J.J.C., W.A., S.L., F.G., W.B.D. and C.G.W. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Marc Abramowicz (marcabra@ulb.ac.be) or * C Geoffrey Woods (cw347@cam.ac.uk) Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (800K) Supplementary Table 1 and Supplementary Figures 1–7 Additional data
• Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture
  - Nat Genet 42(11):1015-1020 (2010)
  Nature Genetics | Letter Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture * Timothy W Yu1, 2, 3, 4, 5, 6, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Ganeshwaran H Mochida1, 2, 3, 4, 5, 6, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * David J Tischfield1, 2, 3, 4, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Sema K Sgaier1, 2, 3, 4, 5, 8 Search for this author in: * NPG journals * PubMed * Google Scholar * Laura Flores-Sarnat9 Search for this author in: * NPG journals * PubMed * Google Scholar * Consolato M Sergi10, 11 Search for this author in: * NPG journals * PubMed * Google Scholar * Meral Topçu12 Search for this author in: * NPG journals * PubMed * Google Scholar * Marie T McDonald13 Search for this author in: * NPG journals * PubMed * Google Scholar * Brenda J Barry1, 2, 3, 4, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Jillian M Felie1, 2, 3, 4, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Christine Sunu1, 2, 3, 4, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * William B Dobyns14 Search for this author in: * NPG journals * PubMed * Google Scholar * Rebecca D Folkerth15 Search for this author in: * NPG journals * PubMed * Google Scholar * A James Barkovich16 Search for this author in: * NPG journals * PubMed * Google Scholar * Christopher A Walsh1, 2, 3, 4, 5, 6christopher.walsh@childrens.harvard.edu Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 42 ,Pages:1015–1020Year published:(2010)DOI:doi:10.1038/ng.683Received27 May 2010Accepted10 September 2010Published online03 October 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Genes associated with human microcephaly, a condition characterized by a small brain, include critical regulators of proliferation, cell fate and DNA repair. We describe a syndrome of congenital microcephaly and diverse defects in cerebral cortical architecture. Genome-wide linkage analysis in two families identified a 7.5-Mb locus on chromosome 19q13.12 containing 148 genes. Targeted high throughput sequence analysis of linked genes in each family yielded > 4,000 DNA variants and implicated a single gene, WDR62, as harboring potentially deleterious changes. We subsequently identified additional WDR62 mutations in four other families. Magnetic resonance imaging and postmortem brain analysis supports important roles for WDR62 in the proliferation and migration of neuronal precursors. WDR62 is a WD40 repeat–containing protein expressed in neuronal precursors as well as in postmitotic neurons in the developing brain and localizes to the spindle poles of dividing cells. The di! verse phenotypes of WDR62 suggest it has central roles in many aspects of cerebral cortical development. View full text Figures at a glance * Figure 1: Pedigrees and radiographic findings in six consanguineous families with MCSG. (–) Shaded symbols denote affected individuals. () LIS-900, a Mexican family with three affected children. () LIS-2600, a Turkish family with two affected children1. () LIS-2500, () MC-1400 and () MC-1600, three Turkish families (not known to be related to LIS-2600 or to each other). () PH-16900, a Saudi family with three affected children; a fourth child (partial shading) had mild speech delay and articulation and attention difficulties but no brain abnormalities. Whole blood DNA was obtained and analyzed from each nuclear family, with the exception of LIS-2601, who died as a fetus. Asterisks denote the two individuals chosen for targeted high-throughput sequencing. (–) MRI features of individuals with MCSG, demonstrating the breadth of cortical phenotypes associated with WDR62. Mid-sagittal T1 sections (–) and axial T1 sections at the level of the insula (–) are shown for LIS-903 (,), LIS-2501 (,), MC-1601 (,) and PH-16903 (,) individuals, as well as a control indi! vidual (,) age matched to LIS-903. Common findings include microcephaly (–,–), anomalies of the corpus callosum (small splenium in and , absent splenium in and thick body in ), simplification of the normal gyral pattern (,,,,,), as well as more variable features such as mild asymmetries of cortical size (), possible heterotopia and cortical clefts (data not shown; Supplementary Note). Scale bar, 5 cm. * Figure 2: Mapping, capture and sequencing of 148 genes in the MCSG locus. () Homozygosity analysis in four pedigrees (LIS-900, LIS-2600, MC-1400 and MC-1600) revealed a 7.5-Mb interval on chromosome 19 bounded by SNP markers rs17581484 and rs4802998. Homozygous SNPs are shown in red or blue, heterozygous SNPs are shown in yellow and SNPs for which no genotype could be assigned are shown in white. The homozygous region contained 148 annotated UCSC genes. () Custom NimbleGen microarrays were designed to target all coding and noncoding regions of the 85 genes in the center of the linkage peak and all exonic regions of the remaining 63 genes (upper green track; the locations of probes on the array are shown on the lower track). These were used to capture genomic DNA and generate sequencing libraries from two individuals, LIS-903 and LIS-2602. () Libraries were sequenced on a Illumina GA II to an average read depth of >200 and a completeness of 88% to 90% (bases covered by ≥ 10 reads). The depth of sequence coverage over the region is shown. * Figure 3: Six WDR62 mutations reported in association with microcephaly with simplified gyri. () Alterations are shown in genomic, coding DNA and protein contexts. The human WDR62 gene consists of 32 exons shown as boxes and encodes a protein of 1,518 amino acids containing 15 WD40 repeats. Black shaded boxes represent untranslated regions, open boxes represent coding regions, and gray shaded boxes represent alternatively spliced exons. Lines connecting the boxes represent introns. The diagram is drawn to scale. Five of the six alleles (from families LIS-900, LIS-2500, LIS-2600, MC-1400, MC-1600 and LIS-2600) disrupt splice sites or cause frame shifts resulting in protein truncations and are likely null alleles. The sixth allele, found in PH-16900, contains the missense alteration p.Val65Met and is a conserved residue (Supplementary Fig. 4). () Illustration of the c.3936_3937insC mutation in LIS-2602 by high throughput sequencing and representative Sanger traces confirming proper segregation. High throughput sequencing data is shown using the Integrated Genome Viewer! . Aligned reads are shown as gray tags shaded by quality score, SNPs are identified by the letter code of the substituted base, and the position of the LIS-2602 single-basepair insertion is denoted by the letter I. Representative Sanger traces confirm this change in the affected individual and show that both parents are heterozygous for the insertional event. Similarly, representative Sanger traces illustrate the c.363delT mutation in LIS-903 and the carrier status of both parents. * Figure 4: WDR62 expression in developing mouse brain and subcellular localization. () In situ hybridization of E14.5 mouse brain with antisense probe to mouse Wdr62. Sense strand (data not shown) showed no specific hybridization. () Higher power view. A strong WDR62 message is seen in the ventricular zone, subventricular zone, ventral portion of the intermediate zone and the ganglionic eminences, with some hybridization in the cortical plate. (–) Confocal microscopy demonstrating WDR62 subcellular localization. (,) Endogenous WDR62 localization in interphase HeLa cells. () Anti-WDR62 (green), also stained with anti γ-tubulin (red) and Hoechst for DNA (blue), showing perinuclear localization surrounding but not overlapping the centrosome. () Co-staining of interphase HeLa cells with anti-WDR62 and anti-GM130 shows localization of both to the Golgi apparatus near the Hoechst-positive nucleus. (–) WDR62 localization in HeLa and HEK cells during the M phase. () Endogenous WDR62 localizes to the spindle poles in M phase HeLa cells, visualized by double lab! eling with γ-tubulin. () Co-staining with antisera to WDR62 and dynein in HEK cells shows WDR62 at the spindle poles and dynein throughout the spindle. () Transfection of C-terminal HA-tagged WDR62 in HEK cells confirms ring-like localization around the centrosome and overlaps with CEP170, another centrosomal protein. () Endogenous WDR62 immunoreactivity surrounds LIS1 but does not overlap fully. * Figure 5: Histopathologic analysis of a 27-week-old human fetus with MCSG. () Hemotoxylin and eosin stained coronal section from the forebrain of a 27-week-old gestational age fetus with microcephaly with simplified gyri (LIS-2601). Section is at the rostral end of the caudate along the A-P axis. Locations of higher magnification views for panels , and are indicated. (,) Hemotoxylin and eosin stained section demonstrating cortical layering. Compared to a 24-week gestational age control fetus (), LIS-2601 has an abnormally thin cortical plate (despite being three weeks older; ), suggestive of a proliferative defect and an absence of normal-appearing layer II and III cells underneath the molecular layer. The dimensions of the marginal zone are relatively preserved. () In addition to a smaller cortical plate, neurons in the cortical plate display abnormal persistence of a radial columnar pattern and disorganized clustering, shown in a Kluver-Barrera stain. () Occasionally, eruptions of neuroglial cells (arrows) through the pial surface into the subara! chnoid space are seen, as are occasional () streaky heterotopia in the intermediate zone and () clusters of small, darkly staining cells in the outer subventricular zone that resemble dividing cells. IZ, intermediate zone; GE, ganglionic eminence; LV, lateral ventricle; bc, body of the caudate; cc, corpus callosum; ctx, cortex; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; MZ, marginal zone; CP, cortical plate; SP, subplate; SVZ, subventricular zone; VZ, ventricular zone. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions GenBank * O43379 * BC054747 Author information * Accession codes * Author information * Supplementary information Affiliations * Division of Genetics, Department of Medicine, Children's Hospital Boston, Boston, Massachusetts, USA. * Timothy W Yu, * Ganeshwaran H Mochida, * David J Tischfield, * Sema K Sgaier, * Brenda J Barry, * Jillian M Felie, * Christine Sunu & * Christopher A Walsh * Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, Massachusetts, USA. * Timothy W Yu, * Ganeshwaran H Mochida, * David J Tischfield, * Sema K Sgaier, * Brenda J Barry, * Jillian M Felie, * Christine Sunu & * Christopher A Walsh * Howard Hughes Medical Institute, Children's Hospital Boston, Boston, Massachusetts, USA. * Timothy W Yu, * Ganeshwaran H Mochida, * David J Tischfield, * Sema K Sgaier, * Brenda J Barry, * Jillian M Felie, * Christine Sunu & * Christopher A Walsh * Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA. * Timothy W Yu, * Ganeshwaran H Mochida, * David J Tischfield, * Sema K Sgaier, * Brenda J Barry, * Jillian M Felie, * Christine Sunu & * Christopher A Walsh * Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA. * Timothy W Yu, * Ganeshwaran H Mochida, * David J Tischfield, * Sema K Sgaier, * Brenda J Barry, * Jillian M Felie, * Christine Sunu & * Christopher A Walsh * Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA. * Timothy W Yu, * Ganeshwaran H Mochida & * Christopher A Walsh * Division of Child Neurology, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. * Timothy W Yu & * Ganeshwaran H Mochida * Bill and Melinda Gates Foundation, New Delhi, India. * Sema K Sgaier * Department of Clinical Neurosciences, Division of Paediatric Neurology, Alberta Children's Hospital, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada. * Laura Flores-Sarnat * Department of Laboratory Medicine and Pathology, University of Alberta Hospital, Walter Mackenzie Health Sciences Centre, Edmonton, Alberta, Canada. * Consolato M Sergi * Institute of Pathology, Medical University of Innsbruck, Innsbruck, Austria. * Consolato M Sergi * Department of Pediatrics Section of Pediatric Neurology, Hacettepe University, Medical Faculty, Ihsan Dogramaci Children's Hospital, Ankara, Turkey. * Meral Topçu * Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, North Carolina, USA. * Marie T McDonald * Division of Genetics, University of Washington at Seattle, Seattle, Washington, USA. * William B Dobyns * Division of Neuropathology, Brigham and Women's Hospital, Boston, Massachusetts, USA. * Rebecca D Folkerth * Department of Radiology, University of California San Francisco, San Francisco, California, USA. * A James Barkovich Contributions T.W.Y. helped characterize MCSG syndrome, designed and performed targeted capture experiments, generated sequencing libraries, designed bioinformatics pipelines, analyzed sequencing data, identified WDR62 mutations, designed WDR62 in situ expression studies, designed, performed and analyzed WDR62 immunohistochemistry studies, helped analyze the LIS-2601 postmortem specimen and wrote the manuscript. G.H.M. helped characterize MCSG syndrome, performed initial genome wide linkage studies and identified the MCSG locus. D.J.T. designed and performed WDR62 immunohistochemistry studies, helped analyze in situ expression studies and helped analyze the LIS-2601 postmortem specimen. S.K.S. helped characterize MCSG syndrome, identified additional affected families, analyzed SNP and microsatellite genotyping and narrowed the MCSG genomic interval. L.F.-S. helped characterize MCSG syndrome and wrote the initial clinical description of the LIS-900 family. C.M.S. identified the LIS-2600 fa! mily and provided clinical information and the LIS-2601 postmortem specimen. M.T. identified the MC-1400 and MC-1600 families and provided clinical information. M.T.M. identified the PH-16900 family and provided clinical information. B.J.B. organized clinical information and subject samples. J.M.F. sequenced WDR62 in families to confirm high throughput sequencing findings and to discover additional alleles. C.S. helped with bioinformatic pipelines and generated constructs for WDR62 in situ expression studies. W.B.D. referred the PH-16900 family. R.D.F. analyzed the LIS-2601 postmortem specimen. A.J.B. reviewed MRIs for characterization of MCSG syndrome. C.A.W. directed the overall research, helped analyze the LIS-2601 postmortem specimen and wrote the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Christopher A Walsh (christopher.walsh@childrens.harvard.edu) Supplementary information * Accession codes * Author information * Supplementary information Movies * Supplementary Movie 1 (468K) Microcephaly, simplified gyri, polymicrogyria, and schizencephaly in a patient with a WDR62 mutation. T1-weighted MRI sequence of a patient (PH-16903) with a homozygous V65M mutation, demonstrating microcephaly, simplified gyri, relatively preserved brain stem and cerebellum, widespread polymicrogyria, and right temporo-parietal open lip schizencephaly. PDF files * Supplementary Text and Figures (3M) Supplementary Note, Supplementary Figures 1–4 and Supplementary Table 1 Additional data
• Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes
  - Nat Genet 42(11):1021-1026 (2010)
  Nature Genetics | Letter Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes * Sabine Endele1, 19 Search for this author in: * NPG journals * PubMed * Google Scholar * Georg Rosenberger2, 19 Search for this author in: * NPG journals * PubMed * Google Scholar * Kirsten Geider3 Search for this author in: * NPG journals * PubMed * Google Scholar * Bernt Popp1 Search for this author in: * NPG journals * PubMed * Google Scholar * Ceyhun Tamer3 Search for this author in: * NPG journals * PubMed * Google Scholar * Irina Stefanova4 Search for this author in: * NPG journals * PubMed * Google Scholar * Mathieu Milh5, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Fanny Kortüm2 Search for this author in: * NPG journals * PubMed * Google Scholar * Angela Fritsch2 Search for this author in: * NPG journals * PubMed * Google Scholar * Friederike K Pientka2, 18 Search for this author in: * NPG journals * PubMed * Google Scholar * Yorck Hellenbroich4 Search for this author in: * NPG journals * PubMed * Google Scholar * Vera M Kalscheuer7 Search for this author in: * NPG journals * PubMed * Google Scholar * Jürgen Kohlhase8 Search for this author in: * NPG journals * PubMed * Google Scholar * Ute Moog9 Search for this author in: * NPG journals * PubMed * Google Scholar * Gudrun Rappold10 Search for this author in: * NPG journals * PubMed * Google Scholar * Anita Rauch1, 18 Search for this author in: * NPG journals * PubMed * Google Scholar * Hans-Hilger Ropers7 Search for this author in: * NPG journals * PubMed * Google Scholar * Sarah von Spiczak11 Search for this author in: * NPG journals * PubMed * Google Scholar * Holger Tönnies12, 18 Search for this author in: * NPG journals * PubMed * Google Scholar * Nathalie Villeneuve13 Search for this author in: * NPG journals * PubMed * Google Scholar * Laurent Villard5, 14 Search for this author in: * NPG journals * PubMed * Google Scholar * Bernhard Zabel15 Search for this author in: * NPG journals * PubMed * Google Scholar * Martin Zenker1, 18 Search for this author in: * NPG journals * PubMed * Google Scholar * Bodo Laube3 Search for this author in: * NPG journals * PubMed * Google Scholar * André Reis1 Search for this author in: * NPG journals * PubMed * Google Scholar * Dagmar Wieczorek16, 20 Search for this author in: * NPG journals * PubMed * Google Scholar * Lionel Van Maldergem17, 20 Search for this author in: * NPG journals * PubMed * Google Scholar * Kerstin Kutsche2, 20kkutsche@uke.de Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 42 ,Pages:1021–1026Year published:(2010)DOI:doi:10.1038/ng.677Received01 April 2010Accepted30 August 2010Published online03 October 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian brain. Two glycine-binding NR1 subunits and two glutamate-binding NR2 subunits each form highly Ca2+-permeable cation channels which are blocked by extracellular Mg2+ in a voltage-dependent manner1. Either GRIN2B or GRIN2A, encoding the NMDA receptor subunits NR2B and NR2A, was found to be disrupted by chromosome translocation breakpoints in individuals with mental retardation and/or epilepsy. Sequencing of GRIN2B in 468 individuals with mental retardation revealed four de novo mutations: a frameshift, a missense and two splice-site mutations. In another cohort of 127 individuals with idiopathic epilepsy and/or mental retardation, we discovered a GRIN2A nonsense mutation in a three-generation family. In a girl with early-onset epileptic encephalopathy, we identified the de novo GRIN2A mutation c.1845C>A predicting the amino acid substitution p.N615K. Analysis of NR1-NR2AN615K (NR2A su! bunit with the p.N615K alteration) receptor currents revealed a loss of the Mg2+ block and a decrease in Ca2+ permeability. Our findings suggest that disturbances in the neuronal electrophysiological balance during development result in variable neurological phenotypes depending on which NR2 subunit of NMDA receptors is affected. View full text Figures at a glance * Figure 1: Disruption of either GRIN2A or GRIN2B in subjects with chromosome translocations and different neurodevelopmental phenotypes. () Physical map of 12p13.1. BAC (RP11-) and fosmid (G248P8) clones used for mapping the breakpoints of subjects with the 9;12 translocation (subject 1) and the 10;12 translocation (subject 2) are indicated by colored bars and the names are given. Red, mapped distal to the translocation breakpoint; green, spanned the breakpoint; blue, mapped proximal to the breakpoint. Exons of GRIN2B are indicated by vertical bars, exon numbers are given and breakpoint regions are shown. () FISH with BAC clones RP11-96K24 and RP11-435K13 on metaphase spreads from lymphocytes of subjects 1 and 2, respectively, yielded split signals. Wild-type and derivative (der) chromosomes are indicated by arrowheads. () Physical map of 16p13.2. BAC (RP11-) clones used for mapping the breakpoint of subject 3-1 with the 16;17 translocation are indicated by colored bars and the names are given. Color codes are the same as in . Exons of GRIN2A are indicated by vertical bars and the exon numbers are given. The ! breakpoint region is indicated. () Segregation of the 16;17 translocation in members of the family with epilepsy. t(16;17) denotes individuals carrying the chromosomal rearrangement, whereas 46,XX and 46,XY denote individuals with a normal karyotype. The index subject is marked by an arrow. NI, chromosomes not investigated. () FISH with BAC clone RP11-77E6 on metaphase spread from lymphocytes from subject 3-1 yielded split signals. Wild-type and derivative (der) chromosomes are indicated by arrowheads. * Figure 2: Transcript analysis for the mutations c.411+1G>A, c.2360-2A>G and c.803_804delCA in GRIN2B and c.652C>T in GRIN2A. () Partial sequence electropherograms of GRIN2B exon 2 obtained from gDNA and cDNA from subjects 4 (c.411+1G>A) and 8 (c.2360-2A>G) and a healthy individual. Both subjects are heterozygous for rs7301328 (c.366C>G) at the gDNA level (upper panel, left and middle). In contrast, we observed monoallelic expression of one SNP allele in cDNA of subjects 4 and 8 (lower panel, left and middle). A control individual showed biallelic expression of the SNP alleles in GRIN2B cDNA (lower panel, right). () Partial sequence electropherograms of GRIN2B exon 3 obtained from gDNA and cDNA of subject 9 (c.803_804delCA). This subject is heterozygous for the 2-bp deletion in gDNA and cDNA. The respective wild-type cDNA sequence from a healthy individual is shown on the right. () Partial sequence electropherograms of exons 4 and 6 of GRIN2A obtained from gDNA and cDNA of subject 6-1. This subject is heterozygous for both the c.652C>T (p.Q218X) nonsense mutation and rs8049651 (c.1275G>A) at the ge! nomic level (upper panel). Sequence analysis of cDNA-derived amplicons revealed monoallelic expression (lower panel). * Figure 3: Structural and functional consequences of missense mutations in GRIN2B and GRIN2A found in subjects with mental retardation and/or epilepsy. () Topology model of an NR1 and an NR2 subunit. Positions of the two alterations p.R682C and p.N615K are indicated by yellow asterisks in the NR2 subunit consisting of an amino-terminal domain (NTD), the ligand-binding domain (LBD) including the S1 and S2 peptide segments, three transmembrane segments (M1, M2 and M3), a re-entrant pore loop (P) and an intracellular carboxy-terminal domain (CTD). Residue R682 in NR2B lies within the glutamate-binding domain, and N615 in NR2A is in the ion channel pore. N, NH2-terminus; C, COOH-terminus. () Model of the LBDs of the NR1-NR2B NMDA receptor shows residue R682 (magenta) within the glutamate-binding NR2B LBD (cyan) together with an adjacent glycine-binding NR1 LBD (green). Enlargement shows the loss of the stabilizing side chain interactions of R682 with D727 and the carbonyl oxygen of G724 upon mutation to cysteine. () Transmembrane arrangement of the NMDA receptor composed of NR1 (green) and NR2A (cyan) subunits (top view). Enlar! gement highlights the predicted repulsive effect of the positive side chains of p.N615K on cation permeability in the pore forming region (side view). () Current-voltage (I–V) relationships of NR1-NR2A receptors (upper panel). Linear I–V curves of NR1-NR2AN615K (red squares) receptor currents reveal a loss in Mg2+-mediated outward rectification of NR1-NR2A (black triangles) receptors. Currents of NR1-NR2A, NR1-NR2A-NR2AN615K and NR1-NR2AN615K receptors show a gradual loss of voltage-dependent Mg2+ inhibition (lower panel). () Differences in the reversal potential (indicated by arrows) of NR1-NR2A (black triangles) and NR1-NR2AN615K (red squares) receptor currents reveal a decrease in Ca2+ permeability of the mutant receptor. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions GenBank * NM_ 000834.3 * NC_000012.11 * NM_001134407.1 * NC_000016.9 Protein Data Bank * 2A5T * 2A5T Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Sabine Endele & * Georg Rosenberger Affiliations * Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany. * Sabine Endele, * Bernt Popp, * Anita Rauch, * Martin Zenker & * André Reis * Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. * Georg Rosenberger, * Fanny Kortüm, * Angela Fritsch, * Friederike K Pientka & * Kerstin Kutsche * Abteilung Molekulare und zelluläre Neurophysiologie, Technische Universität Darmstadt, Darmstadt, Germany. * Kirsten Geider, * Ceyhun Tamer & * Bodo Laube * Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany. * Irina Stefanova & * Yorck Hellenbroich * INSERM, U910, Faculté de Médecine de la Timone, Marseille, France. * Mathieu Milh & * Laurent Villard * Department of Paediatric Neurology, Hôpital Timone-Enfants, Marseille, France. * Mathieu Milh * Department of Human Molecular Genetics, Max-Planck-Institute for Molecular Genetics, Berlin, Germany. * Vera M Kalscheuer & * Hans-Hilger Ropers * Center for Human Genetics, Freiburg, Germany. * Jürgen Kohlhase * Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany. * Ute Moog * Department of Human Molecular Genetics, University of Heidelberg, Heidelberg, Germany. * Gudrun Rappold * Department of Neuropaediatrics, University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany. * Sarah von Spiczak * Institute of Human Genetics, University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany. * Holger Tönnies * Hôpital Henri Gastaut, Centre Saint Paul, Marseille, France. * Nathalie Villeneuve * Université de la Méditerranée, Marseille, France. * Laurent Villard * University Hospital Freiburg, Centre for Pediatrics and Adolescent Medicine and Institute of Human Genetics, Freiburg, Germany. * Bernhard Zabel * Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany. * Dagmar Wieczorek * Centre de Génétique Humaine, Université de Liège, Liège, Belgium. * Lionel Van Maldergem * Present addresses: Institut für Physiologie, Universität zu Lübeck, Lübeck, Germany (F.K.P.), Institute of Medical Genetics, University of Zurich, Zurich, Switzerland (A. Rauch), Robert Koch-Institut, Berlin, Germany (H.T.), Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany (M.Z.). * Friederike K Pientka, * Anita Rauch, * Holger Tönnies & * Martin Zenker * These authors jointly directed this work. * Dagmar Wieczorek, * Lionel Van Maldergem & * Kerstin Kutsche Contributions Mutation analysis: S.E., B.P. and G. Rosenberger. Transcript analysis: K.K. and G. Rosenberger. Functional analysis of NMDA receptors: K.G. and B.L. NMDA receptor modeling: C.T. and B.L. Subject ascertainment: Y.H., L.V.M., M.M., U.M., G. Rappold, A. Rauch, S.v.S., I.S., N.V., L.V., D.W., B.Z. and M.Z. FISH analysis and breakpoint mapping: A.F., V.M.K., F.K., F.K.P. and H.-H.R. Array CGH analysis: J.K. and H.T. Manuscript writing: K.K., V.M.K., B.L., L.V.M., A. Reis, G. Rosenberger and D.W. Study design: K.K., L.V.M., A. Reis, G. Rosenberger and D.W. All authors contributed to the final version of the paper. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Kerstin Kutsche (kkutsche@uke.de) Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (524K) Supplementary Figures 1–5, Supplementary Tables 1–8 and Supplementary Note Additional data
• Genome-wide patterns of genetic variation among elite maize inbred lines
  - Nat Genet 42(11):1027-1030 (2010)
  Nature Genetics | Letter Genome-wide patterns of genetic variation among elite maize inbred lines * Jinsheng Lai1, 2, 7jlai@cau.edu.cn Search for this author in: * NPG journals * PubMed * Google Scholar * Ruiqiang Li3, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Xun Xu3, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Weiwei Jin2, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Mingliang Xu2, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Hainan Zhao1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Zhongkai Xiang1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Weibin Song1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Kai Ying4 Search for this author in: * NPG journals * PubMed * Google Scholar * Mei Zhang1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Yinping Jiao1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Peixiang Ni3 Search for this author in: * NPG journals * PubMed * Google Scholar * Jianguo Zhang3 Search for this author in: * NPG journals * PubMed * Google Scholar * Dong Li3 Search for this author in: * NPG journals * PubMed * Google Scholar * Xiaosen Guo3 Search for this author in: * NPG journals * PubMed * Google Scholar * Kaixiong Ye3 Search for this author in: * NPG journals * PubMed * Google Scholar * Min Jian3 Search for this author in: * NPG journals * PubMed * Google Scholar * Bo Wang3 Search for this author in: * NPG journals * PubMed * Google Scholar * Huisong Zheng3 Search for this author in: * NPG journals * PubMed * Google Scholar * Huiqing Liang3 Search for this author in: * NPG journals * PubMed * Google Scholar * Xiuqing Zhang3 Search for this author in: * NPG journals * PubMed * Google Scholar * Shoucai Wang2 Search for this author in: * NPG journals * PubMed * Google Scholar * Shaojiang Chen2 Search for this author in: * NPG journals * PubMed * Google Scholar * Jiansheng Li2 Search for this author in: * NPG journals * PubMed * Google Scholar * Yan Fu4 Search for this author in: * NPG journals * PubMed * Google Scholar * Nathan M Springer5 Search for this author in: * NPG journals * PubMed * Google Scholar * Huanming Yang3 Search for this author in: * NPG journals * PubMed * Google Scholar * Jian Wang3 Search for this author in: * NPG journals * PubMed * Google Scholar * Jingrui Dai2 Search for this author in: * NPG journals * PubMed * Google Scholar * Patrick S Schnable4schnable@iastate.edu Search for this author in: * NPG journals * PubMed * Google Scholar * Jun Wang3, 6wangj@genomics.cn Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 42 ,Pages:1027–1030Year published:(2010)DOI:doi:10.1038/ng.684Received16 October 2009Accepted13 September 2010Published online24 October 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg We have resequenced a group of six elite maize inbred lines, including the parents of the most productive commercial hybrid in China. This effort uncovered more than 1,000,000 SNPs, 30,000 indel polymorphisms and 101 low-sequence-diversity chromosomal intervals in the maize genome. We also identified several hundred complete genes that show presence/absence variation among these resequenced lines. We discuss the potential roles of complementation of presence/absence variations and other deleterious mutations in contributing to heterosis. High-density SNP and indel polymorphism markers reported here are expected to be a valuable resource for future genetic studies and the molecular breeding of this important crop. View full text Figures at a glance * Figure 1: Genetic background of three sequenced inbred lines. () Pedigrees of three resequenced inbred lines. The female parent of each cross is listed first. The name of one parent of Zheng58 is not recorded and is termed 'Inbred X'. Resequenced inbred lines are underlined. () Reconstructed recombination events in inbred lines 478 and Zheng58 as they were derived from their parental lines. * Figure 2: Annotation of large-effect SNPs. The numbers (shown by bar lengths) of large-effect SNPs for selected groups of genes are displayed. All the gene families shown were significantly abundant in large-effect SNPs (χ2 test, P < 0.01). * Figure 3: Genome-wide distribution of sequence diversity level, gene density, zero-diversity genes and selected genes on chromosome 4. Other chromosomes are shown in Supplementary Figure 2. Sequence diversity level (Watterson's θ per site12, yellow line; Tajima's π per site28, gray shading) and gene density (black line) are plotted using 1-Mb sliding windows. Regions of low genetic diversity are highlighted in green. Zero-diversity genes are shown by vertical blue bars. Red asterisks mark the positions of three genes known to show evidence of selection. * Figure 4: Numbers of PAVs relative to the B73 reference genome. Inbred lines Zheng58, 5003 and 478 were pooled for this analysis because they are members of the same heterotic group. The remaining three inbred lines were from three other heterotic groups. The numbers of PAVs in each of the four heterotic groups sampled in this study are shown in parentheses. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions GenBank * SRA010130 * ss181800510 * ss184955572 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Jinsheng Lai, * Ruiqiang Li, * Xun Xu, * Weiwei Jin & * Mingliang Xu Affiliations * State Key Lab of Agrobiotechnology, China Agricultural University, Beijing, China. * Jinsheng Lai, * Hainan Zhao, * Zhongkai Xiang, * Weibin Song, * Mei Zhang & * Yinping Jiao * National Maize Improvement Center, China Agricultural University, Beijing, China. * Jinsheng Lai, * Weiwei Jin, * Mingliang Xu, * Hainan Zhao, * Zhongkai Xiang, * Weibin Song, * Mei Zhang, * Yinping Jiao, * Shoucai Wang, * Shaojiang Chen, * Jiansheng Li & * Jingrui Dai * BGI-Shenzhen, Shenzhen, China. * Ruiqiang Li, * Xun Xu, * Peixiang Ni, * Jianguo Zhang, * Dong Li, * Xiaosen Guo, * Kaixiong Ye, * Min Jian, * Bo Wang, * Huisong Zheng, * Huiqing Liang, * Xiuqing Zhang, * Huanming Yang, * Jian Wang & * Jun Wang * Center for Plant Genomics, Iowa State University, Ames, Iowa, USA. * Kai Ying, * Yan Fu & * Patrick S Schnable * Department of Plant Biology, University of Minnesota, Saint Paul, Minnesota, USA. * Nathan M Springer * Department of Biology, University of Copenhagen, Copenhagen, Denmark. * Jun Wang Contributions J. Lai, Jun Wang, R.L., J.D. and P.S.S. managed the project. X.X., H. Zhao, Z.X., W.S., M.Z., Y.J., P.N., M.J., B.W., H. Zheng, H.L. and X.Z. performed experiments and sequencing. J. Lai, Jun Wang, R.L., X.X., Jian Wang and H.Y. designed the analyses. X.X., R.L., W.J., M.X., K. Ying, J.Z., D.L., X.G., K. Ye, S.W., S.C., J. Li and Y.F. performed data analyses. J. Lai, P.S.S., N.M.S., Jun Wang, K. Ying and X.X. wrote the paper. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Jun Wang (wangj@genomics.cn) or * Jinsheng Lai (jlai@cau.edu.cn) or * Patrick S Schnable (schnable@iastate.edu) Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (3M) Supplementary Figures 1–3 and Supplementary Tables 1–5 Additional data