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• Supersequencing the supercontrols
  - Nat Genet 43(11):1041 (2011)
  Nature Genetics | Editorial Supersequencing the supercontrols Journal name:Nature GeneticsVolume: 43,Page:1041Year published:(2011)DOI:doi:10.1038/ng.996Published online27 October 2011 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg The $10m Archon Genomics X PRIZE presented by MEDCO will reward rapid and accurate sequencing of the genomic DNA of 100 centenarians. With this choice, the technological competition will provide highly scrutinized and publicly available reference sequences that will let us focus on the genes behind healthy aging. The start date and rules of competition have been announced for this long-awaited prize contest (p 1055) together with the contest validation protocol developed by community consultation and expert review (see Editorial, Nat. Genet.43, 173, 2011). As the prize contest might well have been carried out using established cell lines, it is gratifying that the case for new scientific and medical discovery has been built into the revised plan for the competition. It is particularly pleasing to us that the consultation process that we helped enable has resulted in the choice of well-phenotyped men and women who have led exceptionally long, healthy lives to participate in donating their genomic information to this contest that challenges our human ingenuity. There are several established ways to incentivize research with funding, tools and public goods. Resource generation projects such as the Human Genome Project and the International HapMap Project have released enormous research potential and have generated unprecedented insights, methodologies and articles. Commercial investment turned sequencing and genotyping experiments into the successful machines of today's genomics research. Lastly, contests such as the Grand Challenges and X PRIZES aim to make the impossible possible by tapping into our competitive spirit, providing an incentive while leaving competitors free to find a route to the goal. However, much biomedical funding is tied to earmarks and donations from groups with an interest in researchers tackling a particular disease, for example where no therapy exists. Many groups now study collections of sick individuals with the aim of understanding the genetic mechanisms of each disease one at a time. A contrary argument says that protective gene variants often provide better insights than disease-causing ones into mechanisms at which to target future therapies. This means that it is worth studying the genomes of very healthy, very old people who may be depleted for common risk variants or even enriched in rare protective variants. Such individuals who have evaded all of the common diseases associated with aging are effectively supercontrols whose genomes deserve to be scrutinized in contrast to the genotypes of the many disease cohorts currently under investigation. Other intended consequences of the contest include the development of tools for the better display and visualization of the assembled and aligned genomes—because the greater the number and diversity of readers thinking about their content, the more chance we have of sparking medically useful insights. We think that one way the unique resource generated by this contest could add momentum to human genomics research and translation is if we could collect ideas for the potential uses of the centenarian sequences from young researchers working in genomics internationally together in dialogue with some of the experts and pioneers of genomics. As the technology nears the state where the prize objectives may be realistically met, we need to be ready to turn the best-scrutinized sequences in the world into usable information. Additional data
• On the evolutionary history of the domesticated apple
  - Nat Genet 43(11):1043-1044 (2011)
  Nature Genetics | Correspondence On the evolutionary history of the domesticated apple * Nicola Harrison1, 2 * Richard J Harrison2, 3 * Affiliations * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:1043–1044Year published:(2011)DOI:doi:10.1038/ng.935Published online27 October 2011 To the Editor: In a recent article, Velasco and colleagues concluded that the European crab apple Malus sylvestris had not contributed significantly to the gene pool of the domestic apple Malus × domestica1, as had previously been suggested2, 3. Our reanalysis of the polymorphism data from the Velasco et al. study suggests that gene flow from M. sylvestris to M. × domestica cannot yet be ruled out, and further study is needed to accurately distinguish introgression (due to secondary contact) from ancestral polymorphism (due to incomplete lineage sorting, ILS). View full text Author information * 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 Affiliations * Royal Botanic Gardens Edinburgh, Edinburgh, UK. * Nicola Harrison * East Malling Research, East Malling, UK. * Nicola Harrison & * Richard J Harrison * Institute of Evolutionary Biology, School of Biological Sciences, Edinburgh, UK. * Richard J Harrison Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Richard J Harrison Author Details * Nicola Harrison Search for this author in: * NPG journals * PubMed * Google Scholar * Richard J Harrison Contact Richard J Harrison Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (667K) Supplementary Methods, Supplementary Figure 1 and Supplementary Tables 1–3 Additional data
• On the evolutionary history of the domesticated apple
  - Nat Genet 43(11):1044-1045 (2011)
  Nature Genetics | Correspondence On the evolutionary history of the domesticated apple * Diego Micheletti1 * Michela Troggio1 * Francesco Salamini1 * Roberto Viola1 * Riccardo Velasco1 * Silvio Salvi1, 2 * Affiliations * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:1044–1045Year published:(2011)DOI:doi:10.1038/ng.983Published online27 October 2011 Micheletti et al. reply: Harrison and Harrison comment on one of the conclusions of our recent article1, namely that Malus × domestica was domesticated from M. sieversii, a wild apple species still common in central Asia2. They suggest that our data do not allow us to exclude M. sylvestris (European crab apple) as one of the progenitors of M. × domestica. View full text Author information * 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 Affiliations * IASMA Research and Innovation Centre, Foundation Edmund Mach, San Michele all'Adige, Italy. * Diego Micheletti, * Michela Troggio, * Francesco Salamini, * Roberto Viola, * Riccardo Velasco & * Silvio Salvi * Current address: Department of Agroenvironmental Sciences and Technologies, University of Bologna, Bologna, Italy. * Silvio Salvi Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Riccardo Velasco Author Details * Diego Micheletti Search for this author in: * NPG journals * PubMed * Google Scholar * Michela Troggio Search for this author in: * NPG journals * PubMed * Google Scholar * Francesco Salamini Search for this author in: * NPG journals * PubMed * Google Scholar * Roberto Viola Search for this author in: * NPG journals * PubMed * Google Scholar * Riccardo Velasco Contact Riccardo Velasco Search for this author in: * NPG journals * PubMed * Google Scholar * Silvio Salvi Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (530K) Supplementary Figures 1 and 2 Additional data
• More to Hi-C than meets the eye
  - Nat Genet 43(11):1047-1048 (2011)
  
• A transposon in tb1 drove maize domestication
  - Nat Genet 43(11):1048-1050 (2011)
  
• Putting the DNA back into DNA methylation
  - Nat Genet 43(11):1050-1051 (2011)
  
• The new date, new format, new goals and new sponsor of the Archon Genomics X PRIZE Competition
  - Nat Genet 43(11):1055-1058 (2011)
  Nature Genetics | Commentary Open The new date, new format, new goals and new sponsor of the Archon Genomics X PRIZE Competition * Larry Kedes1 * Grant Campany1 * AffiliationsJournal name:Nature GeneticsVolume: 43,Pages:1055–1058Year published:(2011)DOI:doi:10.1038/ng.988Published online27 October 2011 The Archon Genomics X Prize contest has been declared for January 2013. Larry Kedes and Grant Campany explain the selection of centenarian genomes for the contest and provide the rules by which the contestants will be judged. View full text Author information * 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 Affiliations * Larry Kedes and Grant Campany are at the X PRIZE Foundation, Playa Vista, California, USA. Competing financial interests Larry Kedes and Grant Campany are paid consultants to the X PRIZE Foundation, Inc. Author Details * Larry Kedes Search for this author in: * NPG journals * PubMed * Google Scholar * Grant Campany Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (479K) Supplementary Methods and Supplementary Note * Supplementary Methods and Supplementary Note (346K) The Archon Genomic X PRIZE presented by MEDCO Rules. http://creativecommons.org/licenses/by-nc-sa/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/ Additional data
• Probabilistic modeling of Hi-C contact maps eliminates systematic biases to characterize global chromosomal architecture
  - Nat Genet 43(11):1059-1065 (2011)
  Nature Genetics | Analysis Probabilistic modeling of Hi-C contact maps eliminates systematic biases to characterize global chromosomal architecture * Eitan Yaffe1 * Amos Tanay1 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:1059–1065Year published:(2011)DOI:doi:10.1038/ng.947Received16 February 2011Accepted25 August 2011Published online16 October 2011 Abstract * Abstract * Author information * Supplementary information Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Hi-C experiments measure the probability of physical proximity between pairs of chromosomal loci on a genomic scale. We report on several systematic biases that substantially affect the Hi-C experimental procedure, including the distance between restriction sites, the GC content of trimmed ligation junctions and sequence uniqueness. To address these biases, we introduce an integrated probabilistic background model and develop algorithms to estimate its parameters and renormalize Hi-C data. Analysis of corrected human lymphoblast contact maps provides genome-wide evidence for interchromosomal aggregation of active chromatin marks, including DNase-hypersensitive sites and transcriptionally active foci. We observe extensive long-range (up to 400 kb) cis interactions at active promoters and derive asymmetric contact profiles next to transcription start sites and CTCF binding sites. Clusters of interacting chromosomal domains suggest physical separation of centromere-proximal and! centromere-distal regions. These results provide a computational basis for the inference of chromosomal architectures from Hi-C experiments. View full text Figures at a glance * Figure 1: Sources of Hi-C biases. (,) Spurious ligation products. Hi-C ligation products (shown schematically in ) are expected to map near restriction sites because of size selection. The sum of distances from mapped Hi-C sequences to the nearest restriction sites was computed for each Hi-C paired read, and the distribution of distances was reconstructed (). Two distinct populations of reads are observed, one distributed as expected for normally ligated and size-selected products (HindIII 78%, NcoI 88%) and one including reads mapped farther away from restriction sites. (,) Fragment lengths and ligation efficiency. Restriction fragments of different lengths are shown schematically in and can be hypothesized to affect crosslinking and ligation efficiency. The trans Hi-C coverage enrichment is defined as the ratio between the observed number of trans contacts and the total number of assayed fragment pairs. Shown are coverage enrichments for all of the fragment ends, binned into 20 equal-sized bins according t! o fragment length (x and y axes). Similar trends are observed for the HindIII and NcoI experiments. (,) Local GC content and Hi-C coverage. Ligation product processing and sequencing may be biased by GC content (). Trans-contact enrichments () stratified according to the GC content of the 200 bp near the restriction fragment ends show intense and contrasting GC biases for the HindIII and NcoI experiments. (,) Effect of sequence uniqueness. Different fractions of uniquely mappable short tags are observed next to restriction sites (). As shown in , this has a direct empirical linear effect on Hi-C coverage. * Figure 2: Model performance. () Shown are distributions of the model correction factors for all combinations of fragment end pairs. The ratio between the tenth and ninetieth percentiles (dashed lines) is over sixfold for both data sets. () Observed (black) and model-predicted (red) trans 1D coverages are depicted along chromosome 1 in 1-Mb resolution, showing low correlation between HindIII and NcoI. () After normalization, the correspondence between the HindIII and NcoI 1D enrichments (ratios of observed and expected coverage) is significantly improved. () Observed trans 1D coverage profiles in NcoI (x axis) and HindIII (y axis) are depicted on the top, showing poor reproducibility (ρ = 0.19). The normalized coverage profiles (ratio of observed to expected reads) are substantially more consistent (bottom, ρ = 0.8). () Shown in black are the log-likelihood scores of the Hi-C probabilistic model (y axis) as a function of the size of the GC-content window used (x axis). For both replicates, a clear peak! is detected when computing GC content using 200 bp (roughly half the size-selection parameter) upstream of the fragment end. No such preference is observed when computing GC content using the sequence downstream of the restriction site (red). Log-likelihood score of a model lacking GC correction is shown as a baseline (dotted lines). () Shown are normalized contact enrichments stratified by regional GC content of the contacting fragment ends. Contacts between fragment ends with similar GC content are enriched. This correlation is observed even though local GC contact is normalized. * Figure 3: Chromosomal architecture around active chromatin. () Fragment ends (NcoI) were binned according to the distance to the nearest H3K4me3, H3K4me1, DNase-hypersensitivity and RNA PolII peak. Bar graphs depict the number of fragment ends in each bin. () Contact enrichment for a pair of bins is defined as the ratio between observed and expected number of trans contacts between all fragment ends associated with the two bins. Enrichments are further normalized by the average values for each row and each column (top bar graphs, see Online Methods) and are depicted as color-coded matrices. In all cases the data reflect a preference for contacts between active foci (bottom left) and between regions that are remote from them (top right). () Shown are the differences in NcoI log2 enrichment values (y axis) when comparing cis contacts involving fragment ends up to 5 kb upstream of a TSS and controls. The data are generated for a set of spatial bins representing contacts over specific chromosomal distances (x axis), separately for TSSs t! hat were marked as active (red) and inactive (blue). Confidence ranges represent propagated binomial standard deviation. () Same as , but for fragment ends within 5 kb downstream of a TSS. () Upstream contact excess was computed by subtracting the downstream contact enrichments profile from the upstream contact enrichment profile. Downstream contact excess was defined conversely. The figure depicts a positive upstream contact excess from the promoter side of active TSSs, and a positive downstream contact excess from the gene side of active TSSs. Excess is observed strongly up to 40 kb, and more weakly for up to 1 Mb from the TSS. * Figure 4: Chromosomal architecture around CTCF binding sites. () Contact matrices were projected on genomic bins generated according to the distance to the nearest CTCF site (NcoI). Enrichment values (normalized as in Fig. 3b) are depicted as a color-coded matrix (column averages are depicted on top). CTCF sites, but also regions that are remote from any CTCF site, are shown to interact more than expected by chance. (,) Shown are the normalized cis-contact profiles (computed as in Fig. 3c,d) for fragment ends located on the 5′ side () or the 3′ side () of CTCF sites. Increased contact probability is observed in a region up to 400 kb from the site, but contacts that are directly crossing the binding sites are depleted. () Upstream contact excess was computed by subtracting the downstream contact enrichments profile from the upstream contact enrichments profile. Downstream contact excess was defined conversely. The data show a positive upstream contact excess when analyzing fragment ends in the 5′ side of a CTCF site, and a positiv! e downstream contact excess when analyzing fragment ends in the 3′ side of a CTCF site. Although the CTCF asymmetry profiles are similar to those observed near active TSSs, the two effects are observed independently, as shown in Supplementary Figure 6b,c. * Figure 5: Contact map clustering. (,) The normalized trans-contact map () and its clustering to three groups () are depicted for the NcoI data set. Chromosomes were divided into three distinct clusters, each characterized by enrichment for intracluster contacts and depletion of intercluster contacts. Cis contacts, which are not used in the clustering, are colored gray. () Properties of contact map clusters. Shown are the distribution of regional GC content (over 1-Mb windows), distance to the nearest DNase, H3K4me3, PolII and CTCF peak, and fibroblast lamina enrichment for the three clusters. The red cluster strongly correlates with marks of active chromatin, and the blue/green clusters correlate with nonactive marks. () The spatial organization of clusters on the chromosomes. Shown are chromosome diagrams, color-coded according to the association of each 1-Mb domain with one of the clusters. The active cluster (red) is distributed over the entire genome but is enriched on the gene-rich and small chromosomes! . The two low-activity clusters divide the genome into centromere-proximal (green) and centromere-distal (blue) fractions. Author information * Abstract * Author information * Supplementary information Affiliations * Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel. * Eitan Yaffe & * Amos Tanay Contributions E.Y. and A.T. conceived and performed the analysis. E.Y and A.T wrote the article. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Amos Tanay Author Details * Eitan Yaffe Search for this author in: * NPG journals * PubMed * Google Scholar * Amos Tanay Contact Amos Tanay Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary Text and Figures (3M) Supplementary Figures 1–8 and Supplementary Table 1 Additional data
• Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease
  - Nat Genet 43(11):1066-1073 (2011)
  Nature Genetics | Article Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease * Manuel A Rivas1, 2, 3 * Mélissa Beaudoin4, 23 * Agnes Gardet5, 23 * Christine Stevens2, 23 * Yashoda Sharma6 * Clarence K Zhang6 * Gabrielle Boucher4 * Stephan Ripke1, 2 * David Ellinghaus7 * Noel Burtt2 * Tim Fennell2 * Andrew Kirby1, 2 * Anna Latiano8 * Philippe Goyette4 * Todd Green2 * Jonas Halfvarson9 * Talin Haritunians10 * Joshua M Korn2 * Finny Kuruvilla2, 11 * Caroline Lagacé4 * Benjamin Neale1, 2 * Ken Sin Lo4 * Phil Schumm12 * Leif Törkvist13 * National Institute of Diabetes and Digestive Kidney Diseases Inflammatory Bowel Disease Genetics Consortium (NIDDK IBDGC) * United Kingdom Inflammatory Bowel Disease Genetics Consortium * International Inflammatory Bowel Disease Genetics Consortium * Marla C Dubinsky15 * Steven R Brant16, 17 * Mark S Silverberg18 * Richard H Duerr19, 20 * David Altshuler1, 2 * Stacey Gabriel2 * Guillaume Lettre4 * Andre Franke7 * Mauro D'Amato21 * Dermot P B McGovern10, 22 * Judy H Cho6 * John D Rioux4 * Ramnik J Xavier1, 2, 5 * Mark J Daly1, 2 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:1066–1073Year published:(2011)DOI:doi:10.1038/ng.952Received05 January 2011Accepted31 August 2011Published online09 October 2011 Abstract * Abstract * Accession codes * Author information * Supplementary information Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10−16, odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, r! are and probably functional variants that could aid functional experiments and predictive models. View full text Figures at a glance * Figure 1: Overview. () Schematic of Crohn's disease rare-variant phenotype project. () Power to detect single-marker rare-variant association in follow-up sample sets. We report the results of the Crohn's disease pooled resequencing project with follow-up genotypes in 13,167 Crohn's disease cases, 12,153 ulcerative colitis cases and 15,331 healthy controls. We report that of the 70 markers successfully genotyped, 22%, 60%, 79%, 88% and 91% have at least 80% power to detect association at minor allele frequency ORs of 1.5, 2, 3, 4 and 5, respectively (see also Supplementary Fig. 3a,b), suggesting that we can address the contribution of rare and low-frequency polymorphisms in GWAS loci to IBD. OR, odds ratio. * Figure 2: CARD9 protective splice-site variant and predicted transcript. Splice-site variant IVS11+1C>G (OR = 0.29), conferring protection against Crohn's disease with predicted transcript. This hypothetical transcript has been observed in spleen, lymph-node and PBMC-derived cDNA libraries. We predict exon 11 to be skipped and the alternative transcript to include exon 9 mRNA sequence continuing to exon 12, including 21 amino acids before reaching a premature stop. * Figure 3: Identification of additional rare variants in NOD2 associated with Crohn's disease. () Five additional risk variants were discovered in NOD2. –log10P and minor allele ORs with 95% confidence intervals indicated with error bars and haplotype block, where D′ taking values from 0–1 (white to red) represents the extent of linkage disequilibrium between markers and numbers represent r2 between markers. () NOD2 haplotypes observed in 700 individuals with overlapping genotype data (R311W, S431L, R702W, R703C, V793M, N852S, M863V, G908R and fs1007insC). S431L and V793M are in tight LD and we regard this as one unit (S431L V793M). R703C is at a higher frequency than R311W although they share haplotypes. Conditional analysis (Supplementary Table 3) demonstrates independent contributions. M863V lies on background haplotype of fs1007insC. * Figure 4: Functional analyses of NOD2 variants. () Schematic of NOD2 protein domains and localization. () HEK293T cells were transfected with NOD2 constructs and fixed using 4% paraformaldehyde at 24 h after transfection. Cells were then subjected to immunofluorescent staining to detect NOD2 and fluorescence was collected using a confocal microscope. Image gallery of a single confocal section. () HEK293T cells were transfected with NOD2 constructs and reporter plasmids encoding firefly luciferase cloned under a promoter containing NF-κB elements and with a plasmid encoding renilla luciferase as a transfection control. After 24 h, cells were stimulated with MDP–L-alanine–L-glutamine (LL) or MDP–L-alanine–D-glutamine (LD) (10 μg/ml) for 6 h. Transcriptional activation was quantified by ratios of firefly luciferase activity to renilla luciferase activity. Data were normalized to unstimulated condition with empty vector transfection. Statistical analyses were carried out using Student's t-test (*P < 0.05). Error bar! s represent 95% CI for fold activation. () Cell lysates were also collected and subjected to western blot analysis to detect NOD2 and actin expression levels. Scale bars, 10 μm. Accession codes * Abstract * Accession codes * Author information * Supplementary information Referenced accessions GenBank * NP_071445.1 * NP_653302.2 * NP_434700.2 * NM_003591 * NP_057051.3 * NP_060735.3 * AAP41817.1 Author information * Abstract * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Mélissa Beaudoin, * Agnes Gardet & * Christine Stevens Affiliations * Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. * Manuel A Rivas, * Stephan Ripke, * Andrew Kirby, * Benjamin Neale, * David Altshuler, * Ramnik J Xavier & * Mark J Daly * Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. * Manuel A Rivas, * Christine Stevens, * Stephan Ripke, * Noel Burtt, * Tim Fennell, * Andrew Kirby, * Todd Green, * Joshua M Korn, * Finny Kuruvilla, * Benjamin Neale, * David Altshuler, * Stacey Gabriel, * Ramnik J Xavier & * Mark J Daly * Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. * Manuel A Rivas * Université de Montréal and Research Centre, Montreal Heart Institute, Montreal, Quebec, Canada. * Mélissa Beaudoin, * Gabrielle Boucher, * Philippe Goyette, * Caroline Lagacé, * Ken Sin Lo, * Guillaume Lettre & * John D Rioux * Gastrointestinal Unit, Center for the Study of the Inflammatory Bowel Disease and Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. * Agnes Gardet & * Ramnik J Xavier * Yale School of Medicine, New Haven, Connecticut, USA. * Yashoda Sharma, * Clarence K Zhang & * Judy H Cho * Institute of Clinical Molecular Biology, Kiel, Germany. * David Ellinghaus & * Andre Franke * Unit of Gastroenterology, Istituto Di Ricovero e Cura a Carattere Scientifico, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy. * Anna Latiano * Örebro University Hospital, Department of Medicine and School of Health and Medical Sciences, Örebro University, Örebro, Sweden. * Jonas Halfvarson * The Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. * Talin Haritunians & * Dermot P B McGovern * Clarus Ventures, Cambridge, Massachusetts, USA. * Finny Kuruvilla * Department of Health Studies, University of Chicago, Chicago, Illinois, USA. * Phil Schumm * Karolinska Institutet, Department of Clinical Science Intervention and Technology, Stockholm, Sweden. * Leif Törkvist * The Pediatric Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California, USA. * Marla C Dubinsky * Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. * Steven R Brant * Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA. * Steven R Brant * Mount Sinai Hospital Inflammatory Bowel Disease Group, University of Toronto, Toronto, Ontario, Canada. * Mark S Silverberg * Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. * Richard H Duerr * Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. * Richard H Duerr * Karolinska Institutet, Department of Biosciences and Nutrition, Stockholm, Sweden. * Mauro D'Amato * Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. * Dermot P B McGovern Consortia * National Institute of Diabetes and Digestive Kidney Diseases Inflammatory Bowel Disease Genetics Consortium (NIDDK IBDGC) * United Kingdom Inflammatory Bowel Disease Genetics Consortium * International Inflammatory Bowel Disease Genetics Consortium Contributions M.A.R. and M.J.D. conceived and designed the study. Functional characterization of NOD2 mutants was coordinated and designed by A.G. and R.J.X. Study subject recruitment and phenotyping was supervised by R.H.D., M.C.D., D.P.B.M., M.D., R.J.X., J.H.C., J.D.R., M.C.D., M.D., A.F., D.E., M.S.S., and A.L. Sequenom assay designs were developed by P.G., T.H., J.H., L.T., and A.K. NIDDK IBDGC BeadXpress typing was coordinated and supervised by Y.S. and J.H.C. The pooled sequencing protocol was designed and established at the Broad Institute by N.B., M.A.R., C.S., D.A., M.J.D. and S.G. NIDDK IBDGC, UK IBDGC and IIBDGC contributed sample collection and Immunochip genotype data for replication. The project was managed by M.A.R., G.L., M.S., J.D.R., J.H.C., R.J.X., D.P.B.M., R.H.D., S.R.B. and M.J.D. C.S. and M.B. carried out pooling. C.S., Y.S., P.G., C.L., D.E. and M.B. carried out genotyping. M.A.R. and M.J.D. designed and carried out the statistical and computational analyses, with! assistance from K.S.L., G.B., B.N., J.M.K., T.G., S.R., F.K., T.F., P.S. and C.K.Z. S.R. assisted with quality control, principal-component analysis and analysis of Immunochip data. Syzygy was developed by M.A.R. and M.J.D. M.J.D. supervised all aspects of the study. The manuscript was written by M.A.R., J.D.R., R.J.X. and M.J.D. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Mark J Daly or * Manuel A Rivas Author Details * Manuel A Rivas Contact Manuel A Rivas Search for this author in: * NPG journals * PubMed * Google Scholar * Mélissa Beaudoin Search for this author in: * NPG journals * PubMed * Google Scholar * Agnes Gardet Search for this author in: * NPG journals * PubMed * Google Scholar * Christine Stevens Search for this author in: * NPG journals * PubMed * Google Scholar * Yashoda Sharma Search for this author in: * NPG journals * PubMed * Google Scholar * Clarence K Zhang Search for this author in: * NPG journals * PubMed * Google Scholar * Gabrielle Boucher Search for this author in: * NPG journals * PubMed * Google Scholar * Stephan Ripke Search for this author in: * NPG journals * PubMed * Google Scholar * David Ellinghaus Search for this author in: * NPG journals * PubMed * Google Scholar * Noel Burtt Search for this author in: * NPG journals * PubMed * Google Scholar * Tim Fennell Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew Kirby Search for this author in: * NPG journals * PubMed * Google Scholar * Anna Latiano Search for this author in: * NPG journals * PubMed * Google Scholar * Philippe Goyette Search for this author in: * NPG journals * PubMed * Google Scholar * Todd Green Search for this author in: * NPG journals * PubMed * Google Scholar * Jonas Halfvarson Search for this author in: * NPG journals * PubMed * Google Scholar * Talin Haritunians Search for this author in: * NPG journals * PubMed * Google Scholar * Joshua M Korn Search for this author in: * NPG journals * PubMed * Google Scholar * Finny Kuruvilla Search for this author in: * NPG journals * PubMed * Google Scholar * Caroline Lagacé Search for this author in: * NPG journals * PubMed * Google Scholar * Benjamin Neale Search for this author in: * NPG journals * PubMed * Google Scholar * Ken Sin Lo Search for this author in: * NPG journals * PubMed * Google Scholar * Phil Schumm Search for this author in: * NPG journals * PubMed * Google Scholar * Leif Törkvist Search for this author in: * NPG journals * PubMed * Google Scholar * National Institute of Diabetes and Digestive Kidney Diseases Inflammatory Bowel Disease Genetics Consortium (NIDDK IBDGC) * United Kingdom Inflammatory Bowel Disease Genetics Consortium * International Inflammatory Bowel Disease Genetics Consortium * Marla C Dubinsky Search for this author in: * NPG journals * PubMed * Google Scholar * Steven R Brant Search for this author in: * NPG journals * PubMed * Google Scholar * Mark S Silverberg Search for this author in: * NPG journals * PubMed * Google Scholar * Richard H Duerr Search for this author in: * NPG journals * PubMed * Google Scholar * David Altshuler Search for this author in: * NPG journals * PubMed * Google Scholar * Stacey Gabriel Search for this author in: * NPG journals * PubMed * Google Scholar * Guillaume Lettre Search for this author in: * NPG journals * PubMed * Google Scholar * Andre Franke Search for this author in: * NPG journals * PubMed * Google Scholar * Mauro D'Amato Search for this author in: * NPG journals * PubMed * Google Scholar * Dermot P B McGovern Search for this author in: * NPG journals * PubMed * Google Scholar * Judy H Cho Search for this author in: * NPG journals * PubMed * Google Scholar * John D Rioux Search for this author in: * NPG journals * PubMed * Google Scholar * Ramnik J Xavier Search for this author in: * NPG journals * PubMed * Google Scholar * Mark J Daly Contact Mark J Daly Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (6M) Supplementary Note, Supplementary Tables 1–7 and Supplementary Figures 1–7 Additional data
• Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome
  - Nat Genet 43(11):1074-1081 (2011)
  Nature Genetics | Article Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome * Claudia M B Carvalho1, 16 * Melissa B Ramocki2, 3, 16 * Davut Pehlivan1 * Luis M Franco1, 14 * Claudia Gonzaga-Jauregui1 * Ping Fang1 * Alanna McCall4 * Eniko Karman Pivnick5 * Stacy Hines-Dowell6 * Laurie H Seaver7, 15 * Linda Friehling8 * Sansan Lee7 * Rosemarie Smith9 * Daniela del Gaudio1 * Marjorie Withers1 * Pengfei Liu1 * Sau Wai Cheung1 * John W Belmont1, 10 * Huda Y Zoghbi1, 2, 11, 12, 13 * P J Hastings1 * James R Lupski1, 3, 4 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:1074–1081Year published:(2011)DOI:doi:10.1038/ng.944Received12 April 2011Accepted23 August 2011Published online02 October 2011 Abstract * Abstract * Author information * Supplementary information Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg We identified complex genomic rearrangements consisting of intermixed duplications and triplications of genomic segments at the MECP2 and PLP1 loci. These complex rearrangements were characterized by a triplicated segment embedded within a duplication in 11 unrelated subjects. Notably, only two breakpoint junctions were generated during each rearrangement formation. All the complex rearrangement products share a common genomic organization, duplication-inverted triplication-duplication (DUP-TRP/INV-DUP), in which the triplicated segment is inverted and located between directly oriented duplicated genomic segments. We provide evidence that the DUP-TRP/INV-DUP structures are mediated by inverted repeats that can be separated by >300 kb, a genomic architecture that apparently leads to susceptibility to such complex rearrangements. A similar inverted repeat–mediated mechanism may underlie structural variation in many other regions of the human genome. We propose a mechanism th! at involves both homology-driven events, via inverted repeats, and microhomologous or nonhomologous events. View full text Figures at a glance * Figure 1: General genomic structure of the complex rearrangement triplications embedded in duplications. () Typical aCGH experimental result for a complex DUP-TRP-DUP rearrangement. Copy-number dosage alteration inferred from aCGH. Transitions of copy-number dosage change, black vertical dotted arrows; size of genomic segments defined by those boundaries vary in each individual complex rearrangement (denoted a–c). Horizontal line at bottom depicts array data. Duplications, red; triplications, blue; inverted repeats, yellow arrowheads. DUPp and TRPp, proximal transition or breakpoint of duplications and triplications, respectively; DUPd and TRPd, distal transition or breakpoint of duplications and triplications, respectively. CEN, centromere; TEL, telomere. () Representative genomic structure determined by further analysis of copy-number breakpoint junctions (jct1 and jct2) in five independent rearrangements using multiple molecular experimental approaches. Genomic segments involved, a–c; respective copy-number gains, a′–c′. Change in orientation of genomic segment, bl! ack arrows. * Figure 2: Individuals carrying complex triplications of chromosome Xq28. () Genomic region harboring alterations involving MECP2. Duplications, red; triplications, blue. Arrows on top of the BAB2769 and BAB2772 rearrangements, position of the transitions to gain according to aCGH; in 6 of 8 cases (BAB2796 and BAB2980 are brothers), the distal transition or breakpoint of both duplications (DUPd) and triplications (TRPd, arrows) cluster within a pair of LCRs (K1 and K2), contrasting with the scattered nature of proximal breakpoints of both duplications (DUPp) and triplications (TRPp) in the same group of subjects. Vertical lines embedded within rearrangement bars, LCRs for which copy numbers were not inferred owing to poor probe coverage. CEN, centromere; TEL, telomere. () aCGH result for family HOU1217. Carrier mother BAB3115 with a de novo complex triplication that was transmitted to her son (BAB3114). * Figure 3: Southern blot analysis of the region flanked by LCRs K1 and K2 at Xq28. LCRs K1 and K2 are ~11.3 kb long, and are located ~38 kb apart in inverted orientation. Their 99% nucleotide sequence identity is probably maintained by frequent gene conversion34. These LCRs flank two genes, FLNA and EMD. () Yellow arrows, inversion: CEN-FLNA/EMD-TEL (H1) and alternative genomic orientation CEN-FLNA/EMD-TEL (H2). An 18.2-kb band is expected to be produced in either inversion haplotype background (H1dup or H2dup) upon duplication and inversion; we hypothesize that the 18.2-kb band includes the breakpoint junction 1 (jct1). () Southern blot results for subjects carrying triplications embedded within duplications, BAB2769, BAB2772, BAB2796/BAB2980, BAB2797, BAB2801, BAB2805 (left) and family HOU1217 (right). NA10851, male carrying reference haplotype (H1); NA15510, heterozygous female carrying both reference and inversion haplotypes (H1 and H2). BAB2771, subject carrying MECP2 duplication not involving LCRs K1 and K2 (H1). * Figure 4: Rearrangement structure for subjects BAB2772, BAB2796/BAB2980, BAB2797, BAB2805 and BAB2769 based on aCGH, Southern blotting and breakpoint sequencing. () Genomic region harboring duplications and triplications spanning chromosome Xq28 according to aCGH. Duplications, red; triplications, blue. Dotted vertical arrows on top of rearrangements indicate position of breakpoints; inverted repeats involved in rearrangement are yellow arrowheads. Segments with copy-number gain, a–c. DUPp and TRPp, proximal transition or breakpoint of duplications and triplications, respectively; DUPd and TRPd, distal transition or breakpoint of duplications and triplications, respectively. () Individual genomic structure of region involved in rearrangement determined by analysis of breakpoint junctions 1 (jct1) and 2 (jct2) for each subject. Black asterisk, junction analyzed by Southern blotting (Fig. 3); all others were sequenced. Genomic positions of junctions are shown. Breakpoint junction sequences are color-coded to highlight segment of origin in reference genome (duplications, red; triplications, blue). Genomic segments involved, –; respe! ctive copy-number gains, ′–′. Microhomologies observed at junctions, underlined black letters; insertions or mismatches at the junctions, green; deletions, dashes; mismatches between the reference sequences and subject sequences, green asterisks. * Figure 5: Proposed model for generation of common DUP-TRP/INV-DUP rearrangement product. () The rearrangement may have occurred during spermatogenesis in the ancestral male on his X chromosome, probably during S or G2 phase. () During replication of the sister chromatid, the replication fork may collapse and induce BIR. () BIR uses homologous recombination to re-establish a new fork using ectopic homology provided by inverted repeats forming jct1. (,) This event initiates replication that forms a length of chromatid in the opposite direction from that in which the fork had been traveling before the collapse (), forming a large inverted duplication (). () If the reversed replication collapses again, or if there is a DSB in the chromatid carrying the inverted duplication, then there is a new DNA end. () In our subject cohort, this new end rejoining (jct2 formation) occurred by either NHEJ requiring a DSB on the original strand followed by ligation of that segment to the end of the rearranged newly replicated strand, or by a replication mechanism such as MMBIR that! requires a new strand annealing and extension to the end of the replicon or the chromosome. () Representative structure obtained after two steps of homologous and nonhomologous mechanisms. Duplicated and triplicated segments, red and blue, respectively. Author information * Abstract * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Claudia M B Carvalho & * Melissa B Ramocki Affiliations * Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. * Claudia M B Carvalho, * Davut Pehlivan, * Luis M Franco, * Claudia Gonzaga-Jauregui, * Ping Fang, * Daniela del Gaudio, * Marjorie Withers, * Pengfei Liu, * Sau Wai Cheung, * John W Belmont, * Huda Y Zoghbi, * P J Hastings & * James R Lupski * Department of Pediatrics, Division of Pediatric Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, Texas, USA. * Melissa B Ramocki & * Huda Y Zoghbi * Texas Children's Hospital, Houston, Texas, USA. * Melissa B Ramocki & * James R Lupski * Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. * Alanna McCall & * James R Lupski * Department of Pediatrics, Division of Clinical Genetics and Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, USA. * Eniko Karman Pivnick * Nursing Administration, Division of Medical Genetics LeBonheur Children's Hospital, Memphis, Tennessee, USA. * Stacy Hines-Dowell * Kapiolani Medical Specialists, Honolulu, Hawaii, USA. * Laurie H Seaver & * Sansan Lee * Children's Medical Associates, Alexandria, Virginia, USA. * Linda Friehling * Division of Genetics, Department of Pediatrics, Maine Medical Center, Portland, Maine, USA. * Rosemarie Smith * Department of Pediatrics, Division of Cardiology, Baylor College of Medicine, Houston, Texas, USA. * John W Belmont * Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA. * Huda Y Zoghbi * Howard Hughes Medical Institute, Chevy Chase, Maryland, USA. * Huda Y Zoghbi * Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA. * Huda Y Zoghbi * Department of Medicine, Baylor College of Medicine, Houston, Texas, USA. * Luis M Franco * Department of Pediatrics, John A. Burns School of Medicine, Honolulu, Hawaii, USA. * Laurie H Seaver Contributions C.M.B.C. conducted high-density aCGH, FISH, breakpoint sequencing, Southern-blotting experiments and data analysis. M.B.R. coordinated human studies, recruited subjects and analyzed clinical data. D.P. and P.L. assisted with high-density aCGH and breakpoint sequencing. L.M.F. and J.W.B. conducted SNP genotyping. E.K.P., S.H.-D., L.S., L.F., S.L. and R.S. recruited and clinically characterized subjects. C.G.-J. assisted with data analysis. P.F. conducted the X-chromosome inactivation studies. A.M. and M.W. carried out cell culture. D.d.G. conducted MLPA. S.W.C. was involved in cytogenetic and clinical aCGH studies. J.R.L. and H.Y.Z. were involved in research design and data analyses. P.J.H. was involved in data analyses. C.M.B.C., M.B.R., P.J.H. and J.R.L. prepared the manuscript. Competing financial interests J.R.L. is on the scientific advisory board of Ion Torrent Systems, is a consultant for Athena Diagnostics and has stock ownership in 23andMe. P.F., D.d.G., S.W.C. and J.R.L. are based in the Department of Molecular and Human Genetics at Baylor College of Medicine, which derives clinical income from the application of high resolution human genome analyses. Corresponding authors Correspondence to: * Melissa B Ramocki or * James R Lupski Author Details * Claudia M B Carvalho Search for this author in: * NPG journals * PubMed * Google Scholar * Melissa B Ramocki Contact Melissa B Ramocki Search for this author in: * NPG journals * PubMed * Google Scholar * Davut Pehlivan Search for this author in: * NPG journals * PubMed * Google Scholar * Luis M Franco Search for this author in: * NPG journals * PubMed * Google Scholar * Claudia Gonzaga-Jauregui Search for this author in: * NPG journals * PubMed * Google Scholar * Ping Fang Search for this author in: * NPG journals * PubMed * Google Scholar * Alanna McCall Search for this author in: * NPG journals * PubMed * Google Scholar * Eniko Karman Pivnick Search for this author in: * NPG journals * PubMed * Google Scholar * Stacy Hines-Dowell Search for this author in: * NPG journals * PubMed * Google Scholar * Laurie H Seaver Search for this author in: * NPG journals * PubMed * Google Scholar * Linda Friehling Search for this author in: * NPG journals * PubMed * Google Scholar * Sansan Lee Search for this author in: * NPG journals * PubMed * Google Scholar * Rosemarie Smith Search for this author in: * NPG journals * PubMed * Google Scholar * Daniela del Gaudio Search for this author in: * NPG journals * PubMed * Google Scholar * Marjorie Withers Search for this author in: * NPG journals * PubMed * Google Scholar * Pengfei Liu Search for this author in: * NPG journals * PubMed * Google Scholar * Sau Wai Cheung Search for this author in: * NPG journals * PubMed * Google Scholar * John W Belmont Search for this author in: * NPG journals * PubMed * Google Scholar * Huda Y Zoghbi Search for this author in: * NPG journals * PubMed * Google Scholar * P J Hastings Search for this author in: * NPG journals * PubMed * Google Scholar * James R Lupski Contact James R Lupski Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary Text and Figures (455K) Supplementary Note, Supplementary Tables 1–4 and Supplementary Figures 1–7 Additional data
• Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function
  - Nat Genet 43(11):1082-1090 (2011)
  Nature Genetics | Article Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function * María Soler Artigas1, 2, 128 * Daan W Loth3, 4, 128 * Louise V Wain1, 2, 128 * Sina A Gharib5, 6, 128 * Ma'en Obeidat7, 128 * Wenbo Tang8, 128 * Guangju Zhai9, 10 * Jing Hua Zhao11 * Albert Vernon Smith12, 13 * Jennifer E Huffman14 * Eva Albrecht15 * Catherine M Jackson16 * David M Evans17 * Gemma Cadby18, 19 * Myriam Fornage20, 21 * Ani Manichaikul22, 23 * Lorna M Lopez24, 25 * Toby Johnson26 * Melinda C Aldrich27, 28 * Thor Aspelund12, 13 * Inês Barroso29, 30 * Harry Campbell31 * Patricia A Cassano8 * David J Couper32 * Gudny Eiriksdottir12 * Nora Franceschini33 * Melissa Garcia34 * Christian Gieger15 * Gauti Kjartan Gislason12 * Ivica Grkovic35 * Christopher J Hammond9 * Dana B Hancock36, 37 * Tamara B Harris34 * Adaikalavan Ramasamy38, 39, 40 * Susan R Heckbert41, 42, 43 * Markku Heliövaara44 * Georg Homuth45 * Pirro G Hysi9 * Alan L James46, 47, 48 * Stipan Jankovic35 * Bonnie R Joubert36 * Stefan Karrasch49 * Norman Klopp50 * Beate Koch51 * Stephen B Kritchevsky52 * Lenore J Launer34 * Yongmei Liu53 * Laura R Loehr33 * Kurt Lohman54 * Ruth J F Loos11 * Thomas Lumley55 * Khalid A Al Balushi7 * Wei Q Ang56 * R Graham Barr57 * John Beilby58, 59 * John D Blakey7 * Mladen Boban60 * Vesna Boraska60 * Jonas Brisman61 * John R Britton62 * Guy G Brusselle63 * Cyrus Cooper64 * Ivan Curjuric65, 66 * Santosh Dahgam61 * Ian J Deary24, 25 * Shah Ebrahim67, 68 * Mark Eijgelsheim3 * Clyde Francks69 * Darya Gaysina70 * Raquel Granell71 * Xiangjun Gu20 * John L Hankinson72 * Rebecca Hardy70 * Sarah E Harris24, 73 * John Henderson71 * Amanda Henry7 * Aroon D Hingorani74 * Albert Hofman3, 75 * Patrick G Holt76 * Jennie Hui48, 59, 77, 78 * Michael L Hunter48, 78 * Medea Imboden65, 66 * Karen A Jameson64 * Shona M Kerr79 * Ivana Kolcic60 * Florian Kronenberg80 * Jason Z Liu81 * Jonathan Marchini81 * Tricia McKeever62 * Andrew D Morris82 * Anna-Carin Olin61 * David J Porteous79 * Dirkje S Postma83 * Stephen S Rich22 * Susan M Ring71 * Fernando Rivadeneira3, 75, 84 * Thierry Rochat85 * Avan Aihie Sayer64 * Ian Sayers7 * Peter D Sly76 * George Davey Smith17 * Akshay Sood86 * John M Starr24, 87 * André G Uitterlinden3, 75, 84 * Judith M Vonk88 * S Goya Wannamethee89 * Peter H Whincup90 * Cisca Wijmenga91 * O Dale Williams92 * Andrew Wong70 * Massimo Mangino9 * Kristin D Marciante6, 41 * Wendy L McArdle71 * Bernd Meibohm93 * Alanna C Morrison21 * Kari E North33 * Ernst Omenaas94 * Lyle J Palmer18, 19 * Kirsi H Pietiläinen95, 96, 97 * Isabelle Pin98, 99, 100 * Ozren Polaek60, 101 * Anneli Pouta102 * Bruce M Psaty6, 41, 42, 43 * Anna-Liisa Hartikainen103 * Taina Rantanen104 * Samuli Ripatti97, 105 * Jerome I Rotter106 * Igor Rudan31, 35, 101 * Alicja R Rudnicka90 * Holger Schulz107 * So-Youn Shin29 * Tim D Spector9 * Ida Surakka97, 105 * Veronique Vitart14 * Henry Völzke108 * Nicholas J Wareham11 * Nicole M Warrington19, 56 * H-Erich Wichmann107, 109, 110 * Sarah H Wild31 * Jemma B Wilk111 * Matthias Wjst112, 113 * Alan F Wright14 * Lina Zgaga31, 114 * Tatijana Zemunik60 * Craig E Pennell56 * Fredrik Nyberg61, 115 * Diana Kuh70 * John W Holloway116, 117 * H Marike Boezen88 * Debbie A Lawlor17 * Richard W Morris89 * Nicole Probst-Hensch65, 66 * The International Lung Cancer Consortium127 * GIANT consortium127 * Jaakko Kaprio44, 96, 97 * James F Wilson31 * Caroline Hayward14 * Mika Kähönen118 * Joachim Heinrich107 * Arthur W Musk47, 48, 78, 119 * Deborah L Jarvis38, 120 * Sven Gläser121 * Marjo-Riitta Järvelin39, 102, 120, 122, 123 * Bruno H Ch Stricker3, 4, 75, 84, 124, 128 * Paul Elliott39, 120, 128 * George T O'Connor125, 126, 128 * David P Strachan90, 128 * Stephanie J London36, 128 * Ian P Hall7, 128 * Vilmundur Gudnason12, 13, 128 * Martin D Tobin1, 2, 128 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:1082–1090Year published:(2011)DOI:doi:10.1038/ng.941Received20 April 2011Accepted19 August 2011Published online25 September 2011 Abstract * Abstract * Author information * Supplementary information Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10−8) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function. View full text Figures at a glance * Figure 1: Study design. We followed up in stage 2 a total of 34 SNPs showing new evidence of association (P < 3 × 10−6) with FEV1 and/or FEV1/FVC in a meta-analysis of the stage 1 studies. Studies with a combined total of 24,737 individuals undertook genotyping and association testing of the top ten SNPs. Seven studies (marked with an asterisk) with a combined total of 11,275 individuals had genome-wide association data and provided results for up to 34 SNPs. Researchers from GS: SFHS (marked with #) undertook genotyping on a 32-SNP multiplex genotyping platform and so included the 32 top ranking SNPs (including proxies and both SNPs from regions that showed association with both FEV1 and FEV1/FVC). This assay failed for one SNP (rs3769124), which was subsequently replaced with the thirty-third SNP (rs4762767). We excluded rs2284746 because of poor clustering. Although rs3743563 was chosen as proxy for rs12447804, which had an effective N < 80% in the stage 1 meta-analysis, researchers from BHS2! were unable to genotype rs3743563 and so undertook genotyping for rs12447804 instead. See Table 1 for definitions of all study abbreviations. * Figure 2: Manhattan plots of association results for FEV1/FVC and FEV1 (analysis stage 1). The Manhattan plots for FEV1/FVC () and FEV1 () are ordered by chromosome position. SNPs for which −log10P > 5 are indicated in red. Newly associated regions that reached genome-wide significance after meta-analysis of stages 1 and 2 are labeled. Author information * Abstract * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * María Soler Artigas, * Daan W Loth, * Louise V Wain, * Sina A Gharib, * Ma'en Obeidat, * Wenbo Tang, * Bruno H Ch Stricker, * Paul Elliott, * George T O'Connor, * David P Strachan, * Stephanie J London, * Ian P Hall, * Vilmundur Gudnason & * Martin D Tobin Affiliations * Department of Health Sciences, University of Leicester, Leicester, UK. * María Soler Artigas, * Louise V Wain & * Martin D Tobin * Department of Genetics, University of Leicester, Leicester, UK. * María Soler Artigas, * Louise V Wain & * Martin D Tobin * Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. * Daan W Loth, * Mark Eijgelsheim, * Albert Hofman, * Fernando Rivadeneira, * André G Uitterlinden & * Bruno H Ch Stricker * Inspectorate of Healthcare, The Hague, The Netherlands. * Daan W Loth & * Bruno H Ch Stricker * Center for Lung Biology, University of Washington, Seattle, Washington, USA. * Sina A Gharib * Department of Medicine, University of Washington, Seattle, Washington, USA. * Sina A Gharib, * Kristin D Marciante & * Bruce M Psaty * Division of Therapeutics and Molecular Medicine, Nottingham Respiratory Biomedical Research Unit, University Hospital of Nottingham, Nottingham, London, UK. * Ma'en Obeidat, * Khalid A Al Balushi, * John D Blakey, * Amanda Henry, * Ian Sayers & * Ian P Hall * Division of Nutritional Sciences, Cornell University Ithaca, New York, USA. * Wenbo Tang & * Patricia A Cassano * Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. * Guangju Zhai, * Christopher J Hammond, * Pirro G Hysi, * Massimo Mangino & * Tim D Spector * Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada. * Guangju Zhai * Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. * Jing Hua Zhao, * Ruth J F Loos & * Nicholas J Wareham * Icelandic Heart Association, Kopavogur, Iceland. * Albert Vernon Smith, * Thor Aspelund, * Gudny Eiriksdottir, * Gauti Kjartan Gislason & * Vilmundur Gudnason * University of Iceland, Reykjavik, Iceland. * Albert Vernon Smith, * Thor Aspelund & * Vilmundur Gudnason * MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK. * Jennifer E Huffman, * Veronique Vitart, * Alan F Wright & * Caroline Hayward * Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. * Eva Albrecht & * Christian Gieger * School of Medicine, University of St. Andrews, St. Andrews, Scotland, UK. * Catherine M Jackson * MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK. * David M Evans, * George Davey Smith & * Debbie A Lawlor * Genetic Epidemiology and Biostatistics Platform, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. * Gemma Cadby & * Lyle J Palmer * Prosserman Centre for Health Research, Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada. * Gemma Cadby, * Lyle J Palmer & * Nicole M Warrington * Brown Foundation Institute of Molecular Medicine, University of Texas at Houston, Houston, Texas, USA. * Myriam Fornage & * Xiangjun Gu * Human Genetics Center, School of Public Health, University of Texas at Houston, Houston, Texas, USA. * Myriam Fornage & * Alanna C Morrison * Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA. * Ani Manichaikul & * Stephen S Rich * Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, Virginia, USA. * Ani Manichaikul * Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK. * Lorna M Lopez, * Ian J Deary, * Sarah E Harris & * John M Starr * Department of Psychology, The University of Edinburgh, Edinburgh, UK. * Lorna M Lopez & * Ian J Deary * Clinical Pharmacology and the Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. * Toby Johnson * Department of Thoracic Surgery, Vanderbilt University, Nashville, Tennessee, USA. * Melinda C Aldrich * Division of Epidemiology, Vanderbilt University, Nashville, Tennessee, USA. * Melinda C Aldrich * Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, UK. * Inês Barroso & * So-Youn Shin * University of Cambridge Metabolic Research Labs, Institute of Metabolic Science Addenbrooke's Hospital, Cambridge, UK. * Inês Barroso * Centre for Population Health Sciences, The University of Edinburgh, Edinburgh, UK. * Harry Campbell, * Igor Rudan, * Sarah H Wild, * Lina Zgaga & * James F Wilson * Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA. * David J Couper * Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA. * Nora Franceschini, * Laura R Loehr & * Kari E North * Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. * Melissa Garcia, * Tamara B Harris & * Lenore J Launer * Croatian Centre for Global Health, The University of Split Medical School, Split, Croatia. * Ivica Grkovic, * Stipan Jankovic & * Igor Rudan * Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA. * Dana B Hancock, * Bonnie R Joubert & * Stephanie J London * Behavioral Health Epidemiology Program, Research Triangle Institute International, Research Triangle Park, North Carolina, USA. * Dana B Hancock * Respiratory Epidemiology and Public Health, Imperial College London, London, UK. * Adaikalavan Ramasamy & * Deborah L Jarvis * Department of Epidemiology and Biostatistics, Imperial College London, London, UK. * Adaikalavan Ramasamy, * Marjo-Riitta Järvelin & * Paul Elliott * Department of Medical and Molecular Genetics, King's College London, Guy's Hospital, London, UK. * Adaikalavan Ramasamy * Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA. * Susan R Heckbert, * Kristin D Marciante & * Bruce M Psaty * Department of Epidemiology, University of Washington, Seattle, Washington, USA. * Susan R Heckbert & * Bruce M Psaty * Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA. * Susan R Heckbert & * Bruce M Psaty * National Institute for Health and Welfare, Helsinki, Finland. * Markku Heliövaara & * Jaakko Kaprio * Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University of Greifswald, Greifswald, Germany. * Georg Homuth * Department of Pulmonary Physiology and Sleep Medicine/West Australian Sleep Disorders Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia. * Alan L James * The School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia. * Alan L James & * Arthur W Musk * Busselton Population Medical Research Foundation, Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia. * Alan L James, * Jennie Hui, * Michael L Hunter & * Arthur W Musk * Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Ludwig-Maximilians-University, Munich, Germany. * Stefan Karrasch * Unit for Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. * Norman Klopp * Department of Internal Medicine B, University Hospital Greifswald, Greifswald, Germany. * Beate Koch * Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. * Stephen B Kritchevsky * Epidemiology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. * Yongmei Liu * Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA. * Kurt Lohman * Department of Statistics, University of Auckland, Auckland, New Zealand. * Thomas Lumley * School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, Australia. * Wei Q Ang, * Nicole M Warrington & * Craig E Pennell * Department of Medicine, Columbia University Medical Center, New York, New York, USA. * R Graham Barr * Department of Surgery and Pathology, University of Western Australia, Nedlands, Western Australia, Australia. * John Beilby * PathWest Laboratory Medicine of Western Australia, Queen Elizabeth II Medical Centre, Nedlands, Western Australia, Australia. * John Beilby & * Jennie Hui * Faculty of Medicine, University of Split, Croatia, Split, Croatia. * Mladen Boban, * Vesna Boraska, * Ivana Kolcic, * Ozren Polaek & * Tatijana Zemunik * Occupational and Environmental Medicine, Department of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. * Jonas Brisman, * Santosh Dahgam, * Anna-Carin Olin & * Fredrik Nyberg * Division of Epidemiology and Public Health, School of Community Health Sciences and Nottingham Respiratory Biomedical Research Unit, University of Nottingham, Nottingham, UK. * John R Britton & * Tricia McKeever * Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium. * Guy G Brusselle * MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK. * Cyrus Cooper, * Karen A Jameson & * Avan Aihie Sayer * Chronic Disease Epidemiology, Swiss Tropical and Public Health (TPH) Institute, Basel, Switzerland. * Ivan Curjuric, * Medea Imboden & * Nicole Probst-Hensch * University of Basel, Switzerland. * Ivan Curjuric, * Medea Imboden & * Nicole Probst-Hensch * Non-Communicable Diseases Epidemiology Unit, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK. * Shah Ebrahim * South Asia Centre for Chronic Disease, New Delhi, India. * Shah Ebrahim * Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands. * Clyde Francks * MRC Unit for Lifelong Health and Ageing, London, UK. * Darya Gaysina, * Rebecca Hardy, * Andrew Wong & * Diana Kuh * School of Social and Community Medicine, University of Bristol, Bristol, UK. * Raquel Granell, * John Henderson, * Susan M Ring & * Wendy L McArdle * Hankinson Consulting, Inc, Athens, Georgia, USA. * John L Hankinson * Medical Genetics Section, The University of Edinburgh, Edinburgh, UK. * Sarah E Harris * Department of Epidemiology and Public Health, University College London, London, UK. * Aroon D Hingorani * Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), The Netherlands. * Albert Hofman, * Fernando Rivadeneira, * André G Uitterlinden & * Bruno H Ch Stricker * Telethon Institute for Child Health Research and Centre for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia. * Patrick G Holt & * Peter D Sly * School of Pathology and Laboratory Medicine, The University of Western Australia, Nedlands, Western Australia, Australia. * Jennie Hui * School of Population Health, University of Western Australia, Nedlands, Western Australia, Australia. * Jennie Hui, * Michael L Hunter & * Arthur W Musk * Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. * Shona M Kerr & * David J Porteous * Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria. * Florian Kronenberg * Department of Statistics, University of Oxford, Oxford, UK. * Jason Z Liu & * Jonathan Marchini * Medical Research Institute, The University of Dundee, Dundee, UK. * Andrew D Morris * Department of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. * Dirkje S Postma * Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. * Fernando Rivadeneira, * André G Uitterlinden & * Bruno H Ch Stricker * Division of Pulmonary Medicine, University Hospitals of Geneva, Geneva, Switzerland. * Thierry Rochat * Department of Medicine, University of New Mexico, Albuquerque, New Mexico, USA. * Akshay Sood * Geriatric Medicine Unit, The University of Edinburgh, Edinburgh, UK. * John M Starr * Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. * Judith M Vonk & * H Marike Boezen * Department of Primary Care and Population Health, University College London, London, UK. * S Goya Wannamethee & * Richard W Morris * Division of Population Health Sciences and Education, St. George's University of London, London, UK. * Peter H Whincup, * Alicja R Rudnicka & * David P Strachan * Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. * Cisca Wijmenga * Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, USA. * O Dale Williams * College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA. * Bernd Meibohm * Centre for Clinical Research, Haukeland University Hospital, Bergen, Norway. * Ernst Omenaas * Obesity Research Unit, Department of Medicine, Division of Internal Medicine, Helsinki University Central Hospital, Helsinki, Finland. * Kirsi H Pietiläinen * Hjelt Institute, Department of Public Health, University of Helsinki, Helsinki, Finland. * Kirsi H Pietiläinen & * Jaakko Kaprio * Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland. * Kirsi H Pietiläinen, * Samuli Ripatti, * Ida Surakka & * Jaakko Kaprio * Pédiatrie, Centre Hospitalier Universitaire (CHU), Grenoble, France. * Isabelle Pin * Inserm U823, Centre de Recherche Albert Bonniot, Grenoble, France. * Isabelle Pin * Université Joseph Fourier, Grenoble, France. * Isabelle Pin * Gen-Info Ltd, Zagreb, Croatia. * Ozren Polaek & * Igor Rudan * Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland. * Anneli Pouta & * Marjo-Riitta Järvelin * Institute of Clinical Medicine, University of Oulu, Oulu, Finland. * Anna-Liisa Hartikainen * Gerontology Research Centre, Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland. * Taina Rantanen * Public Health Genomics Unit, Department Of Chronic Disease Prevention, The National Institute for Health and Welfare, Helsinki, Finland. * Samuli Ripatti & * Ida Surakka * Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. * Jerome I Rotter * Institute of Epidemiology I, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. * Holger Schulz, * H-Erich Wichmann & * Joachim Heinrich * Institute for Community Medicine, Study of Health In Pomerania (SHIP)/Clinical Epidemiological Research, University of Greifswald, Greifswald, Germany. * Henry Völzke * Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany. * H-Erich Wichmann * Klinikum Grosshadern, Munich, Germany. * H-Erich Wichmann * Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. * Jemma B Wilk * Institute of Lung Biology and Disease, Comprehensive Pneumology Center, Helmholtz Zentrum München, Neuherberg, Germany. * Matthias Wjst * Institute for Medical Statistics and Epidemiology (IMSE), Technical University Munich, Munich, Germany. * Matthias Wjst * Andrija Stampar School of Public Health, Faculty of Medicine, University of Zagreb, Zagreb, Croatia. * Lina Zgaga * AstraZeneca Research and Development, Mölndal, Sweden. * Fredrik Nyberg * Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK. * John W Holloway * Infection, Inflammation and Immunity, Faculty of Medicine, University of Southampton, Southampton, UK. * John W Holloway * Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland. * Mika Kähönen * Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia. * Arthur W Musk * MRC Health Protection Agency (HPA) Centre for Environment and Health, Imperial College London, London, UK. * Deborah L Jarvis, * Marjo-Riitta Järvelin & * Paul Elliott * University Hospital Greifswald, Department of Internal Medicine B, Greifswald, Germany. * Sven Gläser * Institute of Health Sciences, University of Oulu, Oulu, Finland. * Marjo-Riitta Järvelin * Biocenter Oulu, University of Oulu, Oulu, Finland. * Marjo-Riitta Järvelin * Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands. * Bruno H Ch Stricker * Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA. * George T O'Connor * The National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA. * George T O'Connor * A full list of members is provided in the Supplementary Note. * $affiliationAuthor Consortia * The International Lung Cancer Consortium * GIANT consortium Contributions Author contributions are listed in alphabetical order. See Supplementary Note for definitions of study acronyms. Stage 1 GWAS, AGES: G.E., M.G., V.G., T.B.H., L.J.L. ARIC: S.J.L., N.F., L.R.L., D.J.C., D.B.H., B.R.J., A.C.M., K.E.N. B58C-T1DGC: D.P.S. B58C -WTCCC: D.P.S. BHS1: A.L.J., A.W.M., L.J.P. CHS: S.A.G., S.R.H., T.L., B.M.P. CROATIA-Korcula: H.C., I.G., S.J., I.R., A.F.W., L.Z. CROATIA-Vis: H.C., C.H., O.P., I.R., A.F.W. ECRHS: D.L.J., E.O., I.P., M.W. EPIC: N.J.W. FHS: J.B.W., G.T.O. FTC: J.K., K.H.P., T. Rantanen. Health ABC: M.C.A., P.A.C., T.B.H., S.B.K., Y.L., B.M. Health 2000: M.H., M.K. KORA F4: J. Heinrich. KORA S3: C.G., H.-E.W. NFBC1966: P.E., A.-L.H., M.-R.J., A.P. ORCADES: H.C., S.H.W., J.F.W., A.F.W. RS: A. Hofman. SHIP: S.G., G.H., B.K., H.V. TwinsUK: T.D.S., G.Z. Stage 2 follow up, ADONIX: J. Brisman., A.-C.O. BHS2: J. Beilby. BRHS: R.W.M., S.G.W., P.H.W. BWHHS: G.D.S., S.E., D.A.L., P.H.W. CARDIA: A.S. CROATIA-Split: M.B., I.K., T.Z. GS: SFHS: C.M.J., S.M.K., A.D.M., D.J.P. HCS: C.C., J.W.H., A.A.S. LBC1936: I.J.D., S.E.H., J.M.S. LifeLines: H.M.B., D.S.P., J.M.! V., C.W. MESA-Lung: R.G.B., J.L.H. Nottingham smokers: I.P.H. NSHD: R.H., D.K. SAPALDIA: N.P.-H., T. Rochat. Look-up studies, ALSPAC: R.G., J. Henderson. ILCCO: ILCCO data. Ox-GSK: C.F., J.M. Stage 1 GWAS, AGES: T.A. ARIC: D.J.C., N.F., L.R.L., A.C.M., K.E.N. B58C-T1DGC: A.R.R., D.P.S. B58C -WTCCC: A.R.R., D.P.S. BHS1: A.L.J., A.W.M., L.J.P. CHS: S.A.G., S.R.H., T.L., B.M.P. CROATIA-Korcula: I.G., S.J., O.P., I.R., L.Z. CROATIA-Vis: H.C., C.H., O.P., I.R., A.F.W. ECRHS: D.L.J., E.O., I.P., M.W. EPIC: N.J.W. FHS: J.B.W., G.T.O. FTC: J.K., K.H.P., T. Rantanen. Health ABC: P.A.C., B.M., W.T. Health 2000: M.H., M.K. KORA F4: S.K., H.S. KORA S3: N.P.-H. NFBC1966: P.E., A.-L.H., M.-R.J., A.P. ORCADES: H.C., S.H.W., J.F.W. RS: G.G.B., M.E., D.W.L., B.H.Ch.S. SHIP: S.G., B.K., H.V. TwinsUK: C.J.H., P.G. Hysi, M.M., T.D.S., G.Z. Stage 2 follow up, ADONIX: J. Brisman, A.-C.O. BHS2: J. Beilby, M.L.H. BRHS: R.W.M., S.G.W., P.H.W. BWHHS: G.D.S., S.E., D.A.L., P.H.W. CARDIA: O.D.W. CROATIA-Split: M.B., I.K., T.Z. GS: SFHS: C.M.J., A.D.M. HCS: C.C., K.A.J., A.A.S. LBC1936: I.J.D., L.M.L., J.M.S. LifeLines: D.S.P., J.M.V. MESA-Lung: R.G.B., J.L.H. Nottingham smokers: K.A.A.B., J! .D.B., I.P.H., A. Henry, M.O., I. Sayers. NSHD: R.H., D.K. SAPALDIA: N.P.-H. Look-up studies, ALSPAC: R.G., J. Henderson. ILCCO: ILCCO. Raine: W.Q.A., P.G. Holt, C.E.P., P.D.S. Stage 1 GWAS, B58C-T1DGC: W.L.M. B58C-WTCCC: W.L.M. BHS1: A.L.J., A.W.M., L.J.P. CHS: S.R.H., B.M.P., J.I.R. CROATIA-Vis: C.H., I.R., A.F.W. ECRHS: M.W. EPIC: I.B., R.J.F.L., J.H.Z. FTC: J.K. Health ABC: Y.L., K.L. Health 2000: S.R., I. Surakka. KORA F4: N.K. KORA S3: C.G. NFBC1966: P.E., A.-L.H., M.-R.J., A.P., A.R. ORCADES: H.C., J.F.W. RS: F.R., A.G.U. SHIP: G.H. TwinsUK: C.J.H., S.-Y.S. Stage 2 follow up, ADONIX: S.D., F.N., A.-C.O. BHS2: J. Beilby, G.C., J.H. BRHS: A.D.H., R.W.M. BWHHS: S.E., D.A.L. CARDIA: M.F., X.G. CROATIA-Split: V.B., T.Z. Gedling: J.R.B., T.M. GS: SFHS: C.M.J., S.M.K., D.J.P. HCS: J.W.H. LBC1936: I.J.D., S.E.H., L.M.L., J.M.S. LifeLines: C.W. MESA-Lung: S.S.R. NSHD: D.K., A.W. SAPALDIA: M.I., F.K. Look-up studies, ALSPAC: S.M.R., W.L.M. ILCCO: ILCCO. Raine: W.Q.A., C.E.P. Stage 1 GWAS, AGES: G.K.G., A.V.S. ARIC: N.F., D.B.H., L.R.L. B58C–T1DGC: A.R.R., D.P.S. B58C -WTCCC: A.R.R., D.P.S. BHS1: N.M.W. CHS: K.D.M., J.I.R. CROATIA-Korcula: C.H., J.E.H., V.V. CROATIA-Vis: C.H., V.V. ECRHS: D.L.J., A.R. EPIC: J.H.Z. FHS: J.B.W. FTC: I. Surakka. Health ABC: P.A.C., Y.L., K.L., W.T. Health 2000: M.K., S.R., I. Surakka. KORA S3: E.A. NFBC1966: A.R. ORCADES: C.H., V.V. RS: M.E., D.W.L. SHIP: S.G., G.H., B.K., H.V. TwinsUK: M.M., G.Z. Stage 2 follow-up studies, ADONIX: S.D., F.N. BHS2: G.C. BRHS: R.W.M. BWHHS: D.A.L. CARDIA: M.F., X.G. HCS: J.W.H., K.A.J. LBC1936: L.M.L. LifeLines: H.M.B. MESA-Lung: A.M., S.S.R. Nottingham smokers: I. Sayers, A. Henry. NSHD: D.G., R.H. SAPALDIA: I.C., M.I. Look-up studies, ALSPAC: D.M.E. ILCCO: ILCCO. Ox-GSK: J.Z.L. Raine: W.Q.A. SpiroMeta consortium: I.P.H., T.J., M.S.A., M.D.T., L.V.W. CHARGE consortium: N.F., S.J.L., D.W.L., K.D.M., A.V.S., W.T., J.B.W. SpiroMeta consortium: I.P.H., M.O., I. Sayers, M.S.A., M.D.T., L.V.W. CHARGE consortium: S.A.G., D.W.L. SpiroMeta consortium: P.E., I.P.H., M.O., M.S.A., D.P.S., M.D.T., L.V.W. CHARGE consortium: S.J.L., D.W.L., S.A.G., G.T.O., V.G., B.H.Ch.S., W.T. Competing financial interests I.B. and spouse own stock in Incyte Ltd and GlaxoSmithKline. F.N. is employed by AstraZeneca R&D, 431 83 Mölndal, Sweden. D.S.P. has received unrestricted research grants from and has been a consultant to AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Nycomed and TEVA. C.F. is a full-time employee of GlaxoSmithKline (GSK), and GSK also funded several aspects of the study as detailed in the Acknowledgements section for Ox-GSK. 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• Identification of genetic elements that autonomously determine DNA methylation states
  - Nat Genet 43(11):1091-1097 (2011)
  Nature Genetics | Article Identification of genetic elements that autonomously determine DNA methylation states * Florian Lienert1, 2 * Christiane Wirbelauer1 * Indrani Som3 * Ann Dean3 * Fabio Mohn1, 4 * Dirk Schübeler1, 2 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:1091–1097Year published:(2011)DOI:doi:10.1038/ng.946Received08 April 2011Accepted25 August 2011Published online02 October 2011 Abstract * Abstract * Author information * Supplementary information Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Cytosine methylation is a repressive, epigenetically propagated DNA modification. Although patterns of DNA methylation seem tightly regulated in mammals, it is unclear how these are specified and to what extent this process entails genetic or epigenetic regulation. To dissect the role of the underlying DNA sequence, we sequentially inserted over 50 different DNA elements into the same genomic locus in mouse stem cells. Promoter sequences of approximately 1,000 bp autonomously recapitulated correct DNA methylation in pluripotent cells. Moreover, they supported proper de novo methylation during differentiation. Truncation analysis revealed that this regulatory potential is contained within small methylation-determining regions (MDRs). MDRs can mediate both hypomethylation and de novo methylation in cis, and their activity depends on developmental state, motifs for DNA-binding factors and a critical CpG density. These results demonstrate that proximal sequence elements are both! necessary and sufficient for regulating DNA methylation and reveal basic constraints of this regulation. View full text Figures at a glance * Figure 1: Ectopic Nanog promoter recapitulates the methylation state of the endogenous promoter. () RNAseq and chromatin immunoprecipitation sequencing (ChIPseq) tracks for H3K4me2 and H3K27me327. Read counts (per 100 bp) are shown for the β-globin locus (left) and a randomly chosen region (kctd15; right) in ES cells and derived neuronal progenitors (NPs). The UCSC CpG island and gene tracks are shown below. () Sequence fragments (gray box) are integrated in the β-globin locus by Cre recombinase. The target site consists of two inverted loxP elements (triangles) flanking a fusion of a hygromycin-resistance (Hy) and a ganciclovir-sensitivity gene (Tk), which is replaced by the sequence of interest. () DNA methylation levels for single CpGs at the inserted 5.7-kb promoter fragment of Nanog are depicted as black (methylated) or white (unmethylated) circles. Every line corresponds to a sequenced bisulfite PCR amplicon. Colored vertical bars summarize these results, as defined by the color legend. () CpG methylation levels at the inserted 1-kb Nanog promoter fragment. () R! NA Pol II occupancy and RNA levels (in ES cells) and H3K4me2 occupancy (in ES and NP cells) at the inserted 1-kb Nanog promoter fragment. ChIP enrichment for RNA Pol II and H3K4me2 was normalized to Hprt. RNA levels were determined using reverse transcription followed by real-time PCR and normalized to Lmnb1. Values at a methylated promoter and at an intergenic region are shown as a comparison. Error bars indicate s.d. from two independent biological replicates. The location of primers for the endogenous and inserted promoter is depicted above. * Figure 2: One-kb elements autonomously set DNA methylation state. () Summary table of inserted fragments. Length of fragments is given in bp. The heat map summarizes DNA methylation levels of endogenous and inserted promoters in ES cells and in NPs, as defined in the color legend. Transcriptional activity of endogenous and inserted promoters is indicated for ES cells. (Endog., endogenous promoter; Insert, inserted promoter element; ND, not determined). () CpG methylation levels in ES cells at the endogenous Hes3 promoter and the inserted 1-kb and 1.6-kb Hes3 fragments. Methylation levels of the regions indicated by a horizontal bar are shown below each fragment. () CpG methylation levels in ES cells at the endogenous and the ectopically inserted Trf promoter. () Comparison of methylation levels between inserted fragment and endogenous promoter, as determined by bisulfite PCR, illustrating the quantitative similarity in DNA methylation levels (see also Supplementary Figs. 1 and 2). * Figure 3: Truncation experiments identify methylation-determining regions. () CpG methylation levels in ES cells at the inserted 1-kb Syt1 promoter and at five truncated versions. Deletion fragments are aligned to the largest insert. () Comparison of methylation levels in ES cells with length of inserted promoter elements and deletion fragments. () CpG methylation levels in stem cells at two inserted 1-kb promoters and at their respective MDRs. * Figure 4: MDR function depends on CpG density and DNA-binding motifs. () Methylation level in ES cells plotted against number of CpGs at inserted promoter elements and deletion fragments. () Methylation level in ES cells plotted against CpG density at inserted promoter elements and E. coli sequence fragments. () Part of the inserted Gtf2a1l promoter sequence (104 of 176 bp) with predicted DNA-binding motifs36, 49 and mutation deletions (in green) indicated. CpG methylation levels in ES cells are shown for each mutated MDR fragment. () Rfx2 occupancy of the inserted Gtf2a1l MDR. ChIP enrichments were normalized to Pdcl2, which also contains a Rfx-binding site38. Error bars indicate s.d. from two independent biological replicates. WT, wild type. * Figure 5: MDRs control de novo methylation and function in cis on heterologous DNA. () CpG methylation levels in ES cells and NPs at MDRs of promoters that get de novo methylated, showing that MDRs are properly reprogrammed. () CpG methylation levels in ES cells at a hybrid of the Mrap promoter fragment with MDRs of the Syt1, Hes3 and Gtf2a1l promoters. In each case the MDR confers partial hypomethylation in cis. This effect is diminished in a hybrid with a mutated Gtf2a1l MDR. () CpG methylation levels at a hybrid of the Gtf2a1l and Syt1 MDRs revealing inhibition of de novo methylation. () Model of MDR function in mediating hypomethylation. Sequence dependence of DNA methylation relies on MDR regions (dark green) that reside within hypomethylated promoters (gray box). MDR activity is dependent on DNA-binding motifs (light green bars) and mediates proximal hypomethylation in cis, probably by protecting against DNA methylation. Author information * Abstract * Author information * Supplementary information Affiliations * Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. * Florian Lienert, * Christiane Wirbelauer, * Fabio Mohn & * Dirk Schübeler * Faculty of Science, University of Basel, Basel, Switzerland. * Florian Lienert & * Dirk Schübeler * Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, USA. * Indrani Som & * Ann Dean * Present address: Institute of Molecular Biotechnology, Vienna, Austria. * Fabio Mohn Contributions F.L. and C.W. performed experiments. I.S. and A.D. generated the target ES cell line. F.L., F.M. and D.S. designed the study, analyzed data and wrote the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Dirk Schübeler Author Details * Florian Lienert Search for this author in: * NPG journals * PubMed * Google Scholar * Christiane Wirbelauer Search for this author in: * NPG journals * PubMed * Google Scholar * Indrani Som Search for this author in: * NPG journals * PubMed * Google Scholar * Ann Dean Search for this author in: * NPG journals * PubMed * Google Scholar * Fabio Mohn Search for this author in: * NPG journals * PubMed * Google Scholar * Dirk Schübeler Contact Dirk Schübeler Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary Text and Figures (3M) Supplementary Figures 1–12 and Supplementary Table 1 Additional data
• A germline variant in the TP53 polyadenylation signal confers cancer susceptibility
  - Nat Genet 43(11):1098-1103 (2011)
  Nature Genetics | Letter A germline variant in the TP53 polyadenylation signal confers cancer susceptibility * Simon N Stacey1, 54 * Patrick Sulem1, 54 * Aslaug Jonasdottir1 * Gisli Masson1 * Julius Gudmundsson1 * Daniel F Gudbjartsson1 * Olafur T Magnusson1 * Sigurjon A Gudjonsson1 * Bardur Sigurgeirsson2, 3 * Kristin Thorisdottir2, 3 * Rafn Ragnarsson2, 3 * Kristrun R Benediktsdottir2, 3 * Bjørn A Nexø4 * Anne Tjønneland5 * Kim Overvad6 * Peter Rudnai7 * Eugene Gurzau8 * Kvetoslava Koppova9 * Kari Hemminki10 * Cristina Corredera11 * Victoria Fuentelsaz12 * Pilar Grasa11 * Sebastian Navarrete13 * Fernando Fuertes13 * Maria D García-Prats14 * Enrique Sanambrosio15 * Angeles Panadero16 * Ana De Juan17 * Almudena Garcia17 * Fernando Rivera17 * Dolores Planelles18 * Virtudes Soriano19 * Celia Requena20 * Katja K Aben21, 22 * Michelle M van Rossum23 * Ruben G H M Cremers21, 24 * Inge M van Oort24 * Dick-Johan van Spronsen25 * Jack A Schalken24 * Wilbert H M Peters26 * Brian T Helfand27 * Jenny L Donovan28 * Freddie C Hamdy29 * Daniel Badescu30 * Ovidiu Codreanu30 * Mariana Jinga30 * Irma E Csiki31 * Vali Constantinescu31 * Paula Badea31 * Ioan N Mates32 * Daniela E Dinu32 * Adrian Constantin32 * Dana Mates31 * Sjofn Kristjansdottir33 * Bjarni A Agnarsson2, 3 * Eirikur Jonsson2, 3 * Rosa B Barkardottir2, 3 * Gudmundur V Einarsson2 * Fridbjorn Sigurdsson2 * Pall H Moller2 * Tryggvi Stefansson2 * Trausti Valdimarsson34 * Oskar T Johannsson2 * Helgi Sigurdsson2 * Thorvaldur Jonsson2 * Jon G Jonasson2, 3, 35 * Laufey Tryggvadottir35 * Terri Rice36 * Helen M Hansen36 * Yuanyuan Xiao37 * Daniel H Lachance38 * Brian Patrick O′Neill38 * Matthew L Kosel39 * Paul A Decker39 * Gudmar Thorleifsson1 * Hrefna Johannsdottir1 * Hafdis T Helgadottir1 * Asgeir Sigurdsson1 * Valgerdur Steinthorsdottir1 * Annika Lindblom40 * Swedish Low-risk Colorectal Cancer Study Group41 * Robert S Sandler42 * Temitope O Keku42 * Karina Banasik43 * Torben Jørgensen44, 45 * Daniel R Witte46 * Torben Hansen43, 47, 48 * Oluf Pedersen43, 45, 48, 49 * Viorel Jinga30 * David E Neal50 * William J Catalona27 * Margaret Wrensch36, 37 * John Wiencke36, 37 * Robert B Jenkins51 * Eduardo Nagore20 * Ulla Vogel52 * Lambertus A Kiemeney21, 24 * Rajiv Kumar10 * José I Mayordomo53 * Jon H Olafsson2, 3 * Augustine Kong1 * Unnur Thorsteinsdottir1, 3 * Thorunn Rafnar1 * Kari Stefansson1, 3 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:1098–1103Year published:(2011)DOI:doi:10.1038/ng.926Received27 May 2011Accepted08 August 2011Published online25 September 2011 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10−17), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10−20). rs78378222 is in the 3′ untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3′-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10−6), glioma (OR = 2.35, P = 1.0 × 10−5) and colorectal adenoma (OR = 1.39, P = 1.6 × 10−4). However, we observed no e! ffect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88–1.27). View full text Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Simon N Stacey & * Patrick Sulem Affiliations * deCODE genetics, Reykjavik, Iceland. * Simon N Stacey, * Patrick Sulem, * Aslaug Jonasdottir, * Gisli Masson, * Julius Gudmundsson, * Daniel F Gudbjartsson, * Olafur T Magnusson, * Sigurjon A Gudjonsson, * Gudmar Thorleifsson, * Hrefna Johannsdottir, * Hafdis T Helgadottir, * Asgeir Sigurdsson, * Valgerdur Steinthorsdottir, * Augustine Kong, * Unnur Thorsteinsdottir, * Thorunn Rafnar & * Kari Stefansson * Landspitali-University Hospital, Reykjavik, Iceland. * Bardur Sigurgeirsson, * Kristin Thorisdottir, * Rafn Ragnarsson, * Kristrun R Benediktsdottir, * Bjarni A Agnarsson, * Eirikur Jonsson, * Rosa B Barkardottir, * Gudmundur V Einarsson, * Fridbjorn Sigurdsson, * Pall H Moller, * Tryggvi Stefansson, * Oskar T Johannsson, * Helgi Sigurdsson, * Thorvaldur Jonsson, * Jon G Jonasson & * Jon H Olafsson * Faculty of Medicine, University of Iceland, Reykjavik, Iceland. * Bardur Sigurgeirsson, * Kristin Thorisdottir, * Rafn Ragnarsson, * Kristrun R Benediktsdottir, * Bjarni A Agnarsson, * Eirikur Jonsson, * Rosa B Barkardottir, * Jon G Jonasson, * Jon H Olafsson, * Unnur Thorsteinsdottir & * Kari Stefansson * Institute of Human Genetics, University of Aarhus, Aarhus, Denmark. * Bjørn A Nexø * Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark. * Anne Tjønneland * Department of Epidemiology, School of Public Health, University of Aarhus, Aarhus, Denmark. * Kim Overvad * National Institute of Environmental Health, Budapest, Hungary. * Peter Rudnai * Environmental Health Centre, Cluj, Cluj-Napoca, Romania. * Eugene Gurzau * State Health Institute, Banska Bystrica, Slovakia. * Kvetoslava Koppova * Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany. * Kari Hemminki & * Rajiv Kumar * Division of Dermatology, University of Zaragoza, Zaragoza, Spain. * Cristina Corredera & * Pilar Grasa * Division of Dermatology, Gregorio Marañon University Hospital, Madrid, Spain. * Victoria Fuentelsaz * Division of Radiation Oncology, University of Zaragoza, Zaragoza, Spain. * Sebastian Navarrete & * Fernando Fuertes * Division of Pathology, San Jorge General Hospital, Huesca, Spain. * Maria D García-Prats * Division of Surgery, General Hospital, Soria, Spain. * Enrique Sanambrosio * Division of Medical Oncology, Ciudad de Coria Hospital, Coria, Spain. * Angeles Panadero * Division of Medical Oncology, Marques de Valdecilla University Hospital, Santander, Spain. * Ana De Juan, * Almudena Garcia & * Fernando Rivera * Laboratory of Histocompatibility-Molecular Biology, Centro de Transfusión de la Comunidad Valenciana, Valencia, Spain. * Dolores Planelles * Department of Oncology, Instituto Valenciano de Oncologia, Valencia, Spain. * Virtudes Soriano * Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain. * Celia Requena & * Eduardo Nagore * Department of Epidemiology, Biostatistics and Health Technology Assessment, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Katja K Aben, * Ruben G H M Cremers & * Lambertus A Kiemeney * Comprehensive Cancer Center The Netherlands, Location Nijmegen, Nijmegen, The Netherlands. * Katja K Aben * Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Michelle M van Rossum * Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Ruben G H M Cremers, * Inge M van Oort, * Jack A Schalken & * Lambertus A Kiemeney * Department of Internal Medicine, Canisius Wilhelmina Ziekenhuis, Nijmegen, The Netherlands. * Dick-Johan van Spronsen * Department of Gastroenterology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. * Wilbert H M Peters * Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. * Brian T Helfand & * William J Catalona * School of Social and Community Medicine, University of Bristol, Bristol, UK. * Jenny L Donovan * Nuffield Department of Surgical Science, University of Oxford, John Radcliffe Hospital, Oxford, UK. * Freddie C Hamdy * University of Medicine and Pharmacy Carol Davila, Bucharest, Romania. * Daniel Badescu, * Ovidiu Codreanu, * Mariana Jinga & * Viorel Jinga * National Institute of Public Health, Bucharest, Romania. * Irma E Csiki, * Vali Constantinescu, * Paula Badea & * Dana Mates * University of Medicine and Pharmacy Carol Davila, St. Mary Surgical Clinic, Bucharest, Romania. * Ioan N Mates, * Daniela E Dinu & * Adrian Constantin * Speglun ehf, Reykjavik, Iceland. * Sjofn Kristjansdottir * Domus Medica, Reykjavik, Iceland. * Trausti Valdimarsson * Icelandic Cancer Registry, Reykjavik, Iceland. * Jon G Jonasson & * Laufey Tryggvadottir * Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA. * Terri Rice, * Helen M Hansen, * Margaret Wrensch & * John Wiencke * Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA. * Yuanyuan Xiao, * Margaret Wrensch & * John Wiencke * Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA. * Daniel H Lachance & * Brian Patrick O′Neill * Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA. * Matthew L Kosel & * Paul A Decker * Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden. * Annika Lindblom * A full list of members is provided in the Acknowledgements Section. * $affiliationAuthor * University Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA. * Robert S Sandler & * Temitope O Keku * The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Copenhagen, Denmark. * Karina Banasik, * Torben Hansen & * Oluf Pedersen * Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. * Torben Jørgensen * Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark. * Torben Jørgensen & * Oluf Pedersen * Steno Diabetes Center, Gentofte, Denmark. * Daniel R Witte * Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark. * Torben Hansen * Hagedorn Research Institute, Gentofte, Denmark. * Torben Hansen & * Oluf Pedersen * Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark. * Oluf Pedersen * Oncology Centre, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK. * David E Neal * Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA. * Robert B Jenkins * National Research Centre for the Working Environment, Copenhagen, Denmark. * Ulla Vogel * Division of Medical Oncology University Hospital, Zaragoza, Spain. * José I Mayordomo Consortia * Swedish Low-risk Colorectal Cancer Study Group Contributions The study was designed and the results were interpreted by S.N.S., P.S., G.M., D.F.G., O.T.M., J.H.O., A.K., U.T., T. Rafnar and K.S. Subject ascertainment and recruitment was carried out by S.N.S., J.G., B.S., K.T., R.R., K.R.B., B.A.N., A.T., K.O., P.R., E.G., K.K., K.H., C.C., V.F., P.G., S.N., F.F., M.D.G.-P., E.S., A.P., A.D.J., A.G., F.R., D.P., V. Soriano, C.R., K.K.A., M.M.v.R., R.G.H.M.C., I.M.v.O., D.-J.v.S., J.A.S., W.H.M.P., B.T.H., J.L.D., F.C.H., D.B., O.C., M.J., I.E.C., V.C., P.B., I.N.M., D.E.D., A.C., D.M., S.K., B.A.A., E.J., R.B.B., G.V.E., F.S., P.H.M., T.S., T.V., O.T.J., H.S., T. Jonsson, J.G.J., L.T., T. Rice, H.M.H., Y.X., D.H.L., B.P.O., M.L.K., P.A.D., V. Steinthorsdottir, A.L., R.S.S., T.O.K., K.B., T. Jørgensen, D.R.W., T.H., O.P., V.J., D.E.N., W.J.C., M.W., J.W., R.B.J., E.N., U.V., L.A.K., R.K., J.I.M., J.H.O., U.T. and T. Rafnar. The sequencing, genotyping and expression analysis was carried out by S.N.S., A.J., J.G., O.T.M., H.J., H.T.H., A! .S. and U.T. The statistical and bioinformatics analysis was carried out by S.N.S., P.S., G.M., D.F.G., S.A.G., G.T. and A.K. S.N.S., P.S., D.F.G., T. Rafnar and K.S. drafted the manuscript. All authors contributed to the final version of the paper. Principal collaborators for the case-control population samples were: S.K. (Colorectal Adenoma), G.V.E. (Iceland Prostate), V.J. (Romania Prostate), D.E.N. (UK Prostate), W.J.C. (US Prostate), M.W. (US UCSF Glioma), R.B.J. (US Mayo Clinic Glioma), E.J. and J.I.M. (Spain BCC and Prostate), U.V. and O.P. (Denmark BCC), L.A.K. (Netherlands Prostate), R.K. (Eastern Europe BCC) and J.H.O. (Iceland BCC). Competing financial interests deCODE Genetics is a private biotechnology company that markets genetic tests. Corresponding authors Correspondence to: * Simon N Stacey or * Kari Stefansson Author Details * Simon N Stacey Contact Simon N Stacey Search for this author in: * NPG journals * PubMed * Google Scholar * Patrick Sulem Search for this author in: * NPG journals * PubMed * Google Scholar * Aslaug Jonasdottir Search for this author in: * NPG journals * PubMed * Google Scholar * Gisli Masson Search for this author in: * NPG journals * PubMed * Google Scholar * Julius Gudmundsson Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel F Gudbjartsson Search for this author in: * NPG journals * PubMed * Google Scholar * Olafur T Magnusson Search for this author in: * NPG journals * PubMed * Google Scholar * Sigurjon A Gudjonsson Search for this author in: * NPG journals * PubMed * Google Scholar * Bardur Sigurgeirsson Search for this author in: * NPG journals * PubMed * Google Scholar * Kristin Thorisdottir Search for this author in: * NPG journals * PubMed * Google 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• Mutations in BRIP1 confer high risk of ovarian cancer
  - Nat Genet 43(11):1104-1107 (2011)
  Nature Genetics | Letter Mutations in BRIP1 confer high risk of ovarian cancer * Thorunn Rafnar1, 21 * Daniel F Gudbjartsson1, 21 * Patrick Sulem1, 21 * Aslaug Jonasdottir1 * Asgeir Sigurdsson1 * Adalbjorg Jonasdottir1 * Soren Besenbacher1 * Pär Lundin1 * Simon N Stacey1 * Julius Gudmundsson1 * Olafur T Magnusson1 * Louise le Roux1 * Gudbjorg Orlygsdottir1 * Hafdis T Helgadottir1 * Hrefna Johannsdottir1 * Arnaldur Gylfason1 * Laufey Tryggvadottir2, 3 * Jon G Jonasson2, 3 * Ana de Juan4 * Eugenia Ortega5 * Jose M Ramon-Cajal6 * Maria D García-Prats7 * Carlos Mayordomo8 * Angeles Panadero9 * Fernando Rivera4 * Katja K H Aben10, 11 * Anne M van Altena12 * Leon F A G Massuger12 * Mervi Aavikko13 * Paula M Kujala14 * Synnöve Staff15, 16 * Lauri A Aaltonen13 * Kristrun Olafsdottir17 * Johannes Bjornsson17 * Augustine Kong1 * Anna Salvarsdottir18 * Hafsteinn Saemundsson18 * Karl Olafsson18 * Kristrun R Benediktsdottir3, 17 * Jeffrey Gulcher1 * Gisli Masson1 * Lambertus A Kiemeney10, 11, 19 * Jose I Mayordomo20 * Unnur Thorsteinsdottir1, 3 * Kari Stefansson1, 3 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:1104–1107Year published:(2011)DOI:doi:10.1038/ng.955Received01 August 2011Accepted02 September 2011Published online02 October 2011 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Ovarian cancer causes more deaths than any other gynecologic malignancy in developed countries. Sixteen million sequence variants, identified through whole-genome sequencing of 457 Icelanders, were imputed to 41,675 Icelanders genotyped using SNP chips, as well as to their relatives. Sequence variants were tested for association with ovarian cancer (N of affected individuals = 656). We discovered a rare (0.41% allelic frequency) frameshift mutation, c.2040_2041insTT, in the BRIP1 (FANCJ) gene that confers an increase in ovarian cancer risk (odds ratio (OR) = 8.13, P = 2.8 × 10−14). The mutation was also associated with increased risk of cancer in general and reduced lifespan by 3.6 years. In a Spanish population, another frameshift mutation in BRIP1, c.1702_1703del, was seen in 2 out of 144 subjects with ovarian cancer and 1 out of 1,780 control subjects (P = 0.016). This allele was also associated with breast cancer (seen in 6/927 cases; P = 0.0079). Ovarian tumors from ! heterozygous carriers of the Icelandic mutation show loss of the wild-type allele, indicating that BRIP1 behaves like a classical tumor suppressor gene in ovarian cancer. View full text Accession codes * Accession codes * Author information * Supplementary information Referenced accessions Entrez Nucleotide * NM_032043 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Thorunn Rafnar, * Daniel F Gudbjartsson & * Patrick Sulem Affiliations * deCODE genetics, Reykjavik, Iceland. * Thorunn Rafnar, * Daniel F Gudbjartsson, * Patrick Sulem, * Aslaug Jonasdottir, * Asgeir Sigurdsson, * Adalbjorg Jonasdottir, * Soren Besenbacher, * Pär Lundin, * Simon N Stacey, * Julius Gudmundsson, * Olafur T Magnusson, * Louise le Roux, * Gudbjorg Orlygsdottir, * Hafdis T Helgadottir, * Hrefna Johannsdottir, * Arnaldur Gylfason, * Augustine Kong, * Jeffrey Gulcher, * Gisli Masson, * Unnur Thorsteinsdottir & * Kari Stefansson * Icelandic Cancer Registry, Reykjavik, Iceland. * Laufey Tryggvadottir & * Jon G Jonasson * Faculty of Medicine, University of Iceland, Reykjavik, Iceland. * Laufey Tryggvadottir, * Jon G Jonasson, * Kristrun R Benediktsdottir, * Unnur Thorsteinsdottir & * Kari Stefansson * Division of Medical Oncology, Marques de Valdecilla University Hospital, Santander, Spain. * Ana de Juan & * Fernando Rivera * Division of Medical Oncology, Arnau de Vilanova University Hospital, Lérida, Spain. * Eugenia Ortega * Division of Gynecology, San Jorge General Hospital, Huesca, Spain. * Jose M Ramon-Cajal * Division of Pathology, San Jorge General Hospital, Huesca, Spain. * Maria D García-Prats * School of Medicine, University of Zaragoza, Zaragoza, Spain. * Carlos Mayordomo * Division of Medical Oncology, Ciudad de Coria Hospital, Coria, Spain. * Angeles Panadero * Comprehensive Cancer Center The Netherlands, Nijmegen, The Netherlands. * Katja K H Aben & * Lambertus A Kiemeney * Department of Epidemiology, Biostatistics and Health Technology Assesment, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Katja K H Aben & * Lambertus A Kiemeney * Department of Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Anne M van Altena & * Leon F A G Massuger * Department of Medical Genetics, Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland. * Mervi Aavikko & * Lauri A Aaltonen * Department of Pathology, Centre for Laboratory Medicine, University of Tampere and Tampere University Hospital, Tampere, Finland. * Paula M Kujala * Laboratory of Cancer Biology, Institute of Biomedical Technology, University of Tampere, Tampere, Finland. * Synnöve Staff * Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland. * Synnöve Staff * Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland. * Kristrun Olafsdottir, * Johannes Bjornsson & * Kristrun R Benediktsdottir * Department of Obstetrics and Gynecology, Landspitali University Hospital, Reykjavik, Iceland. * Anna Salvarsdottir, * Hafsteinn Saemundsson & * Karl Olafsson * Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Lambertus A Kiemeney * Division of Medical Oncology, University Hospital, Zaragoza, Spain. * Jose I Mayordomo Contributions The study was designed and supervised by T.R., D.F.G., P.S., U.T. and K.S. Statistical analysis was carried out by D.F.G, P.S., S.B. and A.K. Patient ascertainment, recruitment, biological material collection and collection of clinical and lifestyle information was organized and carried out by L.T., J.G.J., A.d.J., E.O., J.M.R.-C., M.D.G.-P., C.M., A.P., F.R., K.K.H.A., A.M.v.A., L.F.A.G.M., M.A., P.M.K., S.S., L.A.A., K. Olafsdottir, J.B., A. Salvarsdottir, H.S., K. Olafsson, K.R.B., J. Gulcher, L.A.K. and J.I.M. Principal investigators for the follow up populations were J.I.M. (Spain), L.A.K. (Netherlands) and L.A.A. and S.S. (Finland). Genotyping and laboratory experiments were designed and carried out by Aslaug Jonasdottir, Adalbjorg Jonasdottir, A. Sigurdsson, S.N.S., J. Gudmundsson, O.T.M., L.l.R., G.O., H.T.H. and H.J. Bioinformatics analysis was carried out by A.G., P.L. and G.M. Authors T.R., D.F.G., P.S., U.T. and K.S. wrote the manuscript. All authors contributed ! to the final version of the paper. Competing financial interests Some of the authors employed by deCODE genetics own stock or stock options in the company. Corresponding authors Correspondence to: * Thorunn Rafnar or * Kari Stefansson Author Details * Thorunn Rafnar Contact Thorunn Rafnar Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel F Gudbjartsson Search for this author in: * NPG journals * PubMed * Google Scholar * Patrick Sulem Search for this author in: * NPG journals * PubMed * Google Scholar * Aslaug Jonasdottir Search for this author in: * NPG journals * PubMed * Google Scholar * Asgeir Sigurdsson Search for this author in: * NPG journals * PubMed * Google Scholar * Adalbjorg Jonasdottir Search for this author in: * NPG journals * PubMed * Google Scholar * Soren Besenbacher Search for this author in: * NPG journals * PubMed * Google Scholar * Pär Lundin Search for this author in: * NPG journals * PubMed * Google Scholar * Simon N Stacey Search for this author in: * NPG journals * PubMed * Google Scholar * Julius Gudmundsson Search for this author in: * NPG journals * PubMed * Google Scholar * Olafur T Magnusson Search for this author in: * NPG journals * PubMed * Google Scholar * Louise le Roux Search for this author in: * NPG journals * PubMed * Google Scholar * Gudbjorg Orlygsdottir Search for this author in: * NPG journals * PubMed * Google Scholar * Hafdis T Helgadottir Search for this author in: * NPG journals * PubMed * Google Scholar * Hrefna Johannsdottir Search for this author in: * NPG journals * PubMed * Google Scholar * Arnaldur Gylfason Search for this author in: * NPG journals * PubMed * Google Scholar * Laufey Tryggvadottir Search for this author in: * NPG journals * PubMed * Google Scholar * Jon G Jonasson Search for this author in: * NPG journals * PubMed * Google Scholar * Ana de Juan Search for this author in: * NPG journals * PubMed * Google Scholar * Eugenia Ortega Search for this author in: * NPG journals * PubMed * Google Scholar * Jose M Ramon-Cajal Search for this author in: * NPG journals * PubMed * Google Scholar * Maria D García-Prats Search for this author in: * NPG journals * PubMed * Google Scholar * Carlos Mayordomo Search for this author in: * NPG journals * PubMed * Google Scholar * Angeles Panadero Search for this author in: * NPG journals * PubMed * Google Scholar * Fernando Rivera Search for this author in: * NPG journals * PubMed * Google Scholar * Katja K H Aben Search for this author in: * NPG journals * PubMed * Google Scholar * Anne M van Altena Search for this author in: * NPG journals * PubMed * Google Scholar * Leon F A G Massuger Search for this author in: * NPG journals * PubMed * Google Scholar * Mervi Aavikko Search for this author in: * NPG journals * PubMed * Google Scholar * Paula M Kujala Search for this author in: * NPG journals * PubMed * Google Scholar * Synnöve Staff Search for this author in: * NPG journals * PubMed * Google Scholar * Lauri A Aaltonen Search for this author in: * NPG journals * PubMed * Google Scholar * Kristrun Olafsdottir Search for this author in: * NPG journals * PubMed * Google Scholar * Johannes Bjornsson Search for this author in: * NPG journals * PubMed * Google Scholar * Augustine Kong Search for this author in: * NPG journals * PubMed * Google Scholar * Anna Salvarsdottir Search for this author in: * NPG journals * PubMed * Google Scholar * Hafsteinn Saemundsson Search for this author in: * NPG journals * PubMed * Google Scholar * Karl Olafsson Search for this author in: * NPG journals * PubMed * Google Scholar * Kristrun R Benediktsdottir Search for this author in: * NPG journals * PubMed * Google Scholar * Jeffrey Gulcher Search for this author in: * NPG journals * PubMed * Google Scholar * Gisli Masson Search for this author in: * NPG journals * PubMed * Google Scholar * Lambertus A Kiemeney Search for this author in: * NPG journals * PubMed * Google Scholar * Jose I Mayordomo Search for this author in: * NPG journals * PubMed * Google Scholar * Unnur Thorsteinsdottir Search for this author in: * NPG journals * PubMed * Google Scholar * Kari Stefansson Contact Kari Stefansson Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (2M) Supplementary Note, Supplementary Tables 1–9 and Supplementary Figures 1–3 Additional data
• Genome-wide association study identifies three new melanoma susceptibility loci
  - Nat Genet 43(11):1108-1113 (2011)
  Nature Genetics | Letter Genome-wide association study identifies three new melanoma susceptibility loci * Jennifer H Barrett1, 51 * Mark M Iles1, 51 * Mark Harland1 * John C Taylor1 * Joanne F Aitken2 * Per Arne Andresen3 * Lars A Akslen4, 5 * Bruce K Armstrong6 * Marie-Francoise Avril7 * Esther Azizi8 * Bert Bakker9 * Wilma Bergman10 * Giovanna Bianchi-Scarrà11 * Brigitte Bressac-de Paillerets12, 13 * Donato Calista14 * Lisa A Cannon-Albright15 * Eve Corda12, 16 * Anne E Cust17, 18 * Tadeusz Dębniak19 * David Duffy20 * Alison M Dunning21 * Douglas F Easton21, 22 * Eitan Friedman8, 23 * Pilar Galan24 * Paola Ghiorzo11 * Graham G Giles17, 25 * Johan Hansson26 * Marko Hocevar27 * Veronica Höiom26 * John L Hopper17 * Christian Ingvar28 * Bart Janssen29 * Mark A Jenkins17 * Göran Jönsson30 * Richard F Kefford6 * Giorgio Landi14 * Maria Teresa Landi31 * Julie Lang32 * Jan Lubiński19 * Rona Mackie32, 33 * Josep Malvehy34 * Nicholas G Martin20 * Anders Molven4, 5 * Grant W Montgomery20 * Frans A van Nieuwpoort10 * Srdjan Novakovic27 * Håkan Olsson30 * Lorenza Pastorino11 * Susana Puig34, 35 * Joan Anton Puig-Butille34, 35 * Juliette Randerson-Moor1 * Helen Snowden1 * Rainer Tuominen26 * Patricia Van Belle36 * Nienke van der Stoep9 * David C Whiteman20 * Diana Zelenika37 * Jiali Han38, 39, 40 * Shenying Fang41 * Jeffrey E Lee42 * Qingyi Wei43 * G Mark Lathrop16, 37 * Elizabeth M Gillanders44 * Kevin M Brown45 * Alisa M Goldstein31 * Peter A Kanetsky46, 47 * Graham J Mann6 * Stuart MacGregor20 * David E Elder36 * Christopher I Amos48 * Nicholas K Hayward20 * Nelleke A Gruis10 * Florence Demenais12, 16, 49 * Julia A Newton Bishop1 * D Timothy Bishop1 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:1108–1113Year published:(2011)DOI:doi:10.1038/ng.959Received17 February 2011Accepted08 September 2011Published online09 October 2011 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10−5 and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10−3: an SNP in ATM (rs1801516, overall P = 3.4 × 10−9), an SNP in MX2 (rs45430, P = 2.9 × 10−9) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 × 10−10). A fou! rth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 × 10−7 under a fixed-effects model and P = 1.2 × 10−3 under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series. View full text Figures at a glance * Figure 1: Manhattan plot of results of Cochran-Armitage (CA) trend test stratified by geographic region with −log10 P values shown. The solid horizontal line indicates a P value of 10−5. Markers within 50 kb of an SNP associated with melanoma are marked in black for those identified in a previous GWAS and replicated here, and in red for those first identified in the current study. The y axis is truncated at P = 10−15, although three SNPs in the MC1R region have stronger P values up to 2.7 × 10−27, as signified by the box and arrow. * Figure 2: Stratified CA trend tests for the three replicated regions on chromosomes 2, 11 and 21. The log10P values are from the CA trend test (stratified by geographical region) for genotyped and imputed SNPs, as indicated on the left-hand vertical axis. SNPs genotyped for all samples are plotted as circles, SNPs imputed for all samples as crosses and SNPs genotyped for some samples and imputed for others (as a result of chip differences) as squares. The most significant genotyped SNP is colored purple (with its name above), and the degree of LD between that SNP and the others is indicated by color according to the key (red being the greatest degree of LD). The estimated recombination rate is given by the blue line and indicated on the right-hand vertical axis. The genes in the region and their positions are given underneath the graph. Plots were produced using LocusZoom27. * Figure 3: Forest plot of the per-allele OR for melanoma for SNPs in the three regions first identified by this study. Plots show the current evidence for effects by geography and by case type (family history, multiple primaries or early onset) in the genome-wide and replication samples. Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Jennifer H Barrett & * Mark M Iles Affiliations * Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, Leeds Cancer Research UK Centre, St James's University Hospital, Leeds, UK. * Jennifer H Barrett, * Mark M Iles, * Mark Harland, * John C Taylor, * Juliette Randerson-Moor, * Helen Snowden, * Julia A Newton Bishop & * D Timothy Bishop * Viertel Centre for Research in Cancer Control, The Cancer Council, Queensland, Spring Hill, Brisbane, Queensland, Australia. * Joanne F Aitken * Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway. * Per Arne Andresen * The Gade Institute, University of Bergen, Bergen, Norway. * Lars A Akslen & * Anders Molven * Deptartment of Pathology, Haukeland University Hospital, Bergen, Norway. * Lars A Akslen & * Anders Molven * Westmead Millennium Institute, Westmead, New South Wales, Australia. * Bruce K Armstrong, * Richard F Kefford & * Graham J Mann * Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, Service de Dermatologie, Université Descartes, Paris, France. * Marie-Francoise Avril * Department of Dermatology and the Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. * Esther Azizi & * Eitan Friedman * Department of Clinical Genetics, Center of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. * Bert Bakker & * Nienke van der Stoep * Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands. * Wilma Bergman, * Frans A van Nieuwpoort & * Nelleke A Gruis * Department of Internal Medicine, University of Genoa, Genoa, Italy. * Giovanna Bianchi-Scarrà, * Paola Ghiorzo & * Lorenza Pastorino * INSERM, U946, Fondation Jean-Dausset–CEPH, Paris, France. * Brigitte Bressac-de Paillerets, * Eve Corda & * Florence Demenais * Département de Biopathologie, Service de Génétique, Institut de Cancérologie Gustave Roussy, Villejuif, France. * Brigitte Bressac-de Paillerets * Dermatology Unit, Maurizio Bufalini Hospital, Cesena, Italy. * Donato Calista & * Giorgio Landi * Division of Genetic Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA. * Lisa A Cannon-Albright * Fondation Jean Dausset–CEPH, Paris, France. * Eve Corda, * G Mark Lathrop & * Florence Demenais * Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, The University of Melbourne, Melbourne, Victoria, Australia. * Anne E Cust, * Graham G Giles, * John L Hopper & * Mark A Jenkins * Cancer Epidemiology and Services Research, Sydney School of Public Health, The University of Sydney, Sydney, New South Wales, Australia. * Anne E Cust * International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland. * Tadeusz Dębniak & * Jan Lubiński * Queensland Institute of Medical Research, Brisbane, Queensland, Australia. * David Duffy, * Nicholas G Martin, * Grant W Montgomery, * David C Whiteman, * Stuart MacGregor & * Nicholas K Hayward * Department of Oncology, University of Cambridge, Cambridge, UK. * Alison M Dunning & * Douglas F Easton * Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. * Douglas F Easton * Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. * Eitan Friedman * UMR U557 Inserm; U1125 Institut national de la Recherche Agronomique, Conservatoire national des arts et métiers, Centre de Recherche en Nutrition Humaine, Ile de France, Bobigny, France. * Pilar Galan * Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia. * Graham G Giles * Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. * Johan Hansson, * Veronica Höiom & * Rainer Tuominen * Institute of Oncology Ljubljana, Ljubljana, Slovenia. * Marko Hocevar & * Srdjan Novakovic * Department of Surgery, University Hospital Lund, Lund, Sweden. * Christian Ingvar * ServiceXS, Leiden, The Netherlands. * Bart Janssen * Department of Oncology, University Hospital Lund, Lund, Sweden. * Göran Jönsson & * Håkan Olsson * Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. * Maria Teresa Landi & * Alisa M Goldstein * Department of Medical Genetics, University of Glasgow, Glasgow, UK. * Julie Lang & * Rona Mackie * Public Health and Health Policy, University of Glasgow, Glasgow, UK. * Rona Mackie * Melanoma Unit, Dermatology Department, Hospital Clinic, Institut de Investigacó Biomèdica August Pi Suñe, Universitat de Barcelona, Barcelona, Spain. * Josep Malvehy, * Susana Puig & * Joan Anton Puig-Butille * Centre of Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain. * Susana Puig & * Joan Anton Puig-Butille * Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. * Patricia Van Belle & * David E Elder * Commissariat à l′Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France. * Diana Zelenika & * G Mark Lathrop * Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. * Jiali Han * Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. * Jiali Han * Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. * Jiali Han * Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. * Shenying Fang * Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. * Jeffrey E Lee * Department of Epidemiology Unit 1365, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. * Qingyi Wei * Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, USA. * Elizabeth M Gillanders * Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Gaithersburg, Maryland, USA. * Kevin M Brown * Centre for Clinical Epidemiology & Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania, USA. * Peter A Kanetsky * Department of Biostatistics & Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. * Peter A Kanetsky * Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. * Christopher I Amos * Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie, Paris, France. * Florence Demenais Contributions J.H.B. and M.M.I. led and carried out the statistical analysis, contributed to the design of the study and were members of the writing team. M. Harland contributed to the design of the study and provided genotyping information. J.C.T. carried out statistical analyses and was a member of the writing team. J.F.A., P.A.A., L.A.A., B.K.A., M.-F.A., E.A., W.B., D.C., A.E.C., D.D., A.M.D., D.F.E., E.F., P. Ghiorzo, G.G.G., M. Hocevar, V.H., C.I., M.A.J., G.J., G.L., M.T.L., J. Lang, R.M., J.M., N.G.M., A.M., G.W.M., S.N., L.P., J.A.P.-B., R.T., N.v.d.S., J. Hansson and D.C.W. contributed to the identification of suitable samples for the study. B.B. contributed to the design of the study and supervised the initial processing of samples. G.B.-S., K.M.B., B.B.-deP., L.A.C.-A., T.D., D.E.E., J. Hansson, J.L.H., R.F.K., J. Lubiński, F.A.v.N., H.O., S.P. and P.V.B. contributed to the design of the study. H.S. and B.J. carried out genotyping and contributed to the interpretation of geno! typing data. P. Galan, J.R.-M. and D.Z. contributed to the interpretation of genotyping data. J. Han contributed results of a confirmatory study. C.I.A., S.F., J.E.L. and Q.W. led and contributed analyses from the Houston study. N.K.H., G.J.M. and S.M. led and contributed results from the Australian study. G.M.L. provided genotyping information and contributed to the interpretation of genotype data. F.D., P.A.K., E.C., A.M.G. and E.M.G. advised on statistical analysis and contributed to the design of the study. N.A.G. was consortium deputy lead and contributed to the design of the study. J.A.N.B. was overall consortium lead and contributed to the design of the study. D.T.B. led the analysis group, contributed to the design of the study and was a member of the writing team. A full list of members is provided in the Supplementary Note online. on behalf of the GenoMEL Consortium Competing financial interests The authors declare no competing financial interests. 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• Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3
  - Nat Genet 43(11):1114-1118 (2011)
  Nature Genetics | Letter Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3 * Stuart MacGregor1 * Grant W Montgomery1 * Jimmy Z Liu1 * Zhen Zhen Zhao1 * Anjali K Henders1 * Mitchell Stark1 * Helen Schmid2 * Elizabeth A Holland2 * David L Duffy1 * Mingfeng Zhang3 * Jodie N Painter1 * Dale R Nyholt1 * Judith A Maskiell4 * Jodie Jetann5 * Megan Ferguson5 * Anne E Cust4, 6 * Mark A Jenkins4 * David C Whiteman1 * Håkan Olsson7, 33 * Susana Puig8, 9 * Giovanna Bianchi-Scarrà10 * Johan Hansson11 * Florence Demenais12, 13 * Maria Teresa Landi14 * Tadeusz Dębniak15 * Rona Mackie16 * Esther Azizi17 * Brigitte Bressac-de Paillerets12, 18 * Alisa M Goldstein14 * Peter A Kanetsky19, 20 * Nelleke A Gruis21 * David E Elder22 * Julia A Newton-Bishop23 * D Timothy Bishop23 * Mark M Iles23 * Per Helsing24 * Christopher I Amos25 * Qingyi Wei25 * Li-E Wang25 * Jeffrey E Lee26 * Abrar A Qureshi3, 27 * Richard F Kefford2 * Graham G Giles28 * Bruce K Armstrong6 * Joanne F Aitken5 * Jiali Han3, 27, 29 * John L Hopper4 * Jeffrey M Trent30, 31 * Kevin M Brown32 * Nicholas G Martin1 * Graham J Mann2 * Nicholas K Hayward1 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:1114–1118Year published:(2011)DOI:doi:10.1038/ng.958Received18 February 2011Accepted08 September 2011Published online09 October 2011 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP–CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10−11, OR in combined replication cohorts of 0.89 (95% CI 0.85–0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10−8). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes fo! r melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density. View full text Figures at a glance * Figure 1: Association results for SNPs directly genotyped in all Australian samples. SNPs with P values exceeding genome-wide significance (P < 5 × 10−8) are shown in black, and SNPs with 5 × 10−8 < P < 1 × 10−6 are shown in blue. The y axis is truncated at 1 × 10−9; however, some SNPs from previously identified loci exceeded this threshold (specifically at ~88 Mb on chromosome 16 near MC1R and at the ASIP locus at 33 Mb on chromosome 20. The significant genome-wide signal on chromosome 9 is in the vicinity of the MTAP/CDKN2A region. * Figure 2: Discovery sample association results at two loci on chromosome 1 for both SNPs directly genotyped in all Australian samples and imputed SNPs. (,) Genotyped SNPs are indicated by filled-in triangles and imputed SNPs by empty circles. The top-ranked SNP at each locus is shown as a filled-in purple diamond. (This SNP is an imputed SNP at both loci.) Imputation P values for all SNPs are plotted. Note imputed and genotyped P values for genotyped SNPs differ slightly, because for the imputed result, analysis was based on dosage scores, whereas with genotyped SNPs, hard genotype calls were used. Association results shown are for the chromosome 1 locus near 149 Mb () and SNPs in the vicinity of the PARP1 association signal (). The color scheme indicates linkage disequilibrium between the most strongly associated SNPs for the 149 Mb and PARP1 regions (shown in purple, rs267735 and rs2695238, respectively) and other genotyped SNPs in the two regions. Author information * Author information * Supplementary information Affiliations * Queensland Institute of Medical Research, Brisbane, Queensland, Australia. * Stuart MacGregor, * Grant W Montgomery, * Jimmy Z Liu, * Zhen Zhen Zhao, * Anjali K Henders, * Mitchell Stark, * David L Duffy, * Jodie N Painter, * Dale R Nyholt, * David C Whiteman, * Nicholas G Martin & * Nicholas K Hayward * Westmead Institute of Cancer Research, University of Sydney at Westmead Millennium Institute and Melanoma Institute Australia, Westmead, New South Wales, Australia. * Helen Schmid, * Elizabeth A Holland, * Richard F Kefford & * Graham J Mann * Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. * Mingfeng Zhang, * Abrar A Qureshi & * Jiali Han * Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, The University of Melbourne, Victoria, Australia. * Judith A Maskiell, * Anne E Cust, * Mark A Jenkins & * John L Hopper * Viertel Centre for Research in Cancer Control, Cancer Council Queensland, Brisbane, Queensland, Australia. * Jodie Jetann, * Megan Ferguson & * Joanne F Aitken * Cancer Epidemiology and Services Research, Sydney School of Public Health, The University of Sydney, New South Wales, Australia. * Anne E Cust & * Bruce K Armstrong * Lund Cancer Center Department of Oncology, University Hospital, Lund, Sweden. * Håkan Olsson * Melanoma Unit, Dermatology Department, Hospital Clínic, Institut de Investigació Biomèdica August Pi Suñe, Universitat de Barcelona, Barcelona, Spain. * Susana Puig * Centre of Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain. * Susana Puig * Department of Internal Medicine, University of Genoa, Genoa, Italy. * Giovanna Bianchi-Scarrà * Department of Oncology-Pathology, Karolinska Institute and Karolinska University Hospital, Solna, Stockholm, Sweden. * Johan Hansson * INSERM, U946, Fondation Jean-Dausset–CEPH, Paris, France. * Florence Demenais & * Brigitte Bressac-de Paillerets * Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie Paris, France. * Florence Demenais * Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA. * Maria Teresa Landi & * Alisa M Goldstein * International Hereditary Cancer Center, Szczecin, Poland. * Tadeusz Dębniak * University of Glasgow Department of Public Health, Glasgow, UK. * Rona Mackie * Department of Dermatology/Dermato-Oncology Unit, Sheba Medical Center, Tel Hashomer, Israel. * Esther Azizi * Service de Génétique, Institut de Cancérologie Gustave Roussy, Villejuif, France. * Brigitte Bressac-de Paillerets * Center for Clinical Epidemiology & Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania, USA. * Peter A Kanetsky * Department of Biostatistics & Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. * Peter A Kanetsky * Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands. * Nelleke A Gruis * Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. * David E Elder * Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, Cancer Research UK Clinical Centre at Leeds, St James's University Hospital, Leeds, UK. * Julia A Newton-Bishop, * D Timothy Bishop & * Mark M Iles * Department of Dermatology, Oslo University Hospital, Oslo, Norway. * Per Helsing * Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. * Christopher I Amos, * Qingyi Wei & * Li-E Wang * Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. * Jeffrey E Lee * Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. * Abrar A Qureshi & * Jiali Han * Cancer Epidemiology Centre, The Cancer Council Victoria, Carlton, Victoria, Australia. * Graham G Giles * Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. * Jiali Han * Genetic Basis of Human Disease Division, The Translational Genomics Research Institute, Phoenix, Arizona, USA. * Jeffrey M Trent * Center for Cancer Genomics and Computational Biology, Van Andel Research Institute, Grand Rapids, Michigan, USA. * Jeffrey M Trent * Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA. * Kevin M Brown * On behalf of the Lund Melanoma Group. * Håkan Olsson Contributions S.M., N.K.H. and K.M.B. wrote the manuscript. G.W.M., N.K.H., K.M.B., J.M.T., A.K.H., Z.Z.Z. and M.S. designed, analyzed and managed the sample preparation and genotyping aspects of the study. S.M. and J.Z.L. performed data analysis. D.C.W., D.L.D., G.W.M., N.K.H., S.M., J.N.P., D.R.N. and N.G.M. oversaw collection of the Queensland samples and contributed to statistical analyses, data interpretation and manuscript preparation. G.J.M., A.E.C., E.A.H., H.S., J.A.M., J.J., M.F., M.A.J., R.F.K., G.G.G., B.K.A., J.F.A. and J.L.H. oversaw sample collection, genotyping and analysis in the AMFS study. D.T.B., J.A.N.-B., M.M.I., H.O., S.P., G.B.-S., J.H., F.D., M.T.L., T.D., R.M., E.A., B.B.-d.P., A.M.G., P.A.K., N.A.G., P.H. and D.E.E. contributed to the collection, genotyping and analysis of the GenoMEL samples. C.I.A., Q.W., L.-E.W. and J.E.L. contributed to the collection, genotyping and analysis of the United States 1–M.D. Anderson Cancer Center samples. A.A.Q., M.Z. and J.H.! contributed to the collection, genotyping and analysis of the United States 2–Harvard samples. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Stuart MacGregor Author Details * Stuart MacGregor Contact Stuart MacGregor Search for this author in: * NPG journals * PubMed * Google Scholar * Grant W Montgomery Search for this author in: * NPG journals * PubMed * Google Scholar * Jimmy Z Liu Search for this author in: * NPG journals * PubMed * Google Scholar * Zhen Zhen Zhao Search for this author in: * NPG journals * PubMed * Google Scholar * Anjali K Henders Search for this author in: * NPG journals * PubMed * Google Scholar * Mitchell Stark Search for this author in: * NPG journals * PubMed * Google Scholar * Helen Schmid Search for this author in: * NPG journals * PubMed * Google Scholar * Elizabeth A Holland Search for this author in: * NPG journals * PubMed * Google Scholar * David L Duffy Search for this author in: * NPG journals * PubMed * Google Scholar * Mingfeng Zhang Search for this author in: * NPG journals * PubMed * Google Scholar * Jodie N Painter Search for this author in: * NPG journals * PubMed * Google Scholar * Dale R Nyholt Search for this author in: * NPG journals * PubMed * Google Scholar * Judith A Maskiell Search for this author in: * NPG journals * PubMed * Google Scholar * Jodie Jetann Search for this author in: * NPG journals * PubMed * Google Scholar * Megan Ferguson Search for this author in: * NPG journals * PubMed * Google Scholar * Anne E Cust Search for this author in: * NPG journals * PubMed * Google Scholar * Mark A Jenkins Search for this author in: * NPG journals * PubMed * Google Scholar * David C Whiteman Search for this author in: * NPG journals * PubMed * Google Scholar * Håkan Olsson Search for this author in: * NPG journals * PubMed * Google Scholar * Susana Puig Search for this author in: * NPG journals * PubMed * Google Scholar * Giovanna Bianchi-Scarrà Search for this author in: * NPG journals * PubMed * Google Scholar * Johan Hansson Search for this author in: * NPG journals * PubMed * Google Scholar * Florence Demenais Search for this author in: * NPG journals * PubMed * Google Scholar * Maria Teresa Landi Search for this author in: * NPG journals * PubMed * Google Scholar * Tadeusz Dębniak Search for this author in: * NPG journals * PubMed * Google Scholar * Rona Mackie Search for this author in: * NPG journals * PubMed * Google Scholar * Esther Azizi Search for this author in: * NPG journals * PubMed * Google Scholar * Brigitte Bressac-de Paillerets Search for this author in: * NPG journals * PubMed * Google Scholar * Alisa M Goldstein Search for this author in: * NPG journals * PubMed * Google Scholar * Peter A Kanetsky Search for this author in: * NPG journals * PubMed * Google Scholar * Nelleke A Gruis Search for this author in: * NPG journals * PubMed * Google Scholar * David E Elder Search for this author in: * NPG journals * PubMed * Google Scholar * Julia A Newton-Bishop Search for this author in: * NPG journals * PubMed * Google Scholar * D Timothy Bishop Search for this author in: * NPG journals * PubMed * Google Scholar * Mark M Iles Search for this author in: * NPG journals * PubMed * Google Scholar * Per Helsing Search for this author in: * NPG journals * PubMed * Google Scholar * Christopher I Amos Search for this author in: * NPG journals * PubMed * Google Scholar * Qingyi Wei Search for this author in: * NPG journals * PubMed * Google Scholar * Li-E Wang Search for this author in: * NPG journals * PubMed * Google Scholar * Jeffrey E Lee Search for this author in: * NPG journals * PubMed * Google Scholar * Abrar A Qureshi Search for this author in: * NPG journals * PubMed * Google Scholar * Richard F Kefford Search for this author in: * NPG journals * PubMed * Google Scholar * Graham G Giles Search for this author in: * NPG journals * PubMed * Google Scholar * Bruce K Armstrong Search for this author in: * NPG journals * PubMed * Google Scholar * Joanne F Aitken Search for this author in: * NPG journals * PubMed * Google Scholar * Jiali Han Search for this author in: * NPG journals * PubMed * Google Scholar * John L Hopper Search for this author in: * NPG journals * PubMed * Google Scholar * Jeffrey M Trent Search for this author in: * NPG journals * PubMed * Google Scholar * Kevin M Brown Search for this author in: * NPG journals * PubMed * Google Scholar * Nicholas G Martin Search for this author in: * NPG journals * PubMed * Google Scholar * Graham J Mann Search for this author in: * NPG journals * PubMed * Google Scholar * Nicholas K Hayward Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (545K) Supplementary Tables 1 and 2, Supplementary Figures 1–5 and Supplementary Note Additional data
• Exon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma
  - Nat Genet 43(11):1119-1126 (2011)
  Nature Genetics | Letter Exon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma * Todd D Prickett1, 11 * Xiaomu Wei1, 11 * Isabel Cardenas-Navia1, 11 * Jamie K Teer2, 3 * Jimmy C Lin4 * Vijay Walia1 * Jared Gartner1 * Jiji Jiang1 * Praveen F Cherukuri2 * Alfredo Molinolo5 * Michael A Davies6, 7 * Jeffrey E Gershenwald8, 9 * Katherine Stemke-Hale7 * Steven A Rosenberg10 * Elliott H Margulies2 * Yardena Samuels1 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:1119–1126Year published:(2011)DOI:doi:10.1038/ng.950Received03 August 2011Accepted26 August 2011Published online25 September 2011 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg G protein-coupled receptors (GPCRs), the largest human gene family, are important regulators of signaling pathways. However, knowledge of their genetic alterations is limited. In this study, we used exon capture and massively parallel sequencing methods to analyze the mutational status of 734 GPCRs in melanoma. This investigation revealed that one family member, GRM3, was frequently mutated and that one of its mutations clustered within one position. Biochemical analysis of GRM3 alterations revealed that mutant GRM3 selectively regulated the phosphorylation of MEK, leading to increased anchorage-independent growth and migration. Melanoma cells expressing mutant GRM3 had reduced cell growth and cellular migration after short hairpin RNA–mediated knockdown of GRM3 or treatment with a selective MEK inhibitor, AZD-6244, which is currently being used in phase 2 clinical trials. Our study yields the most comprehensive map of genetic alterations in the GPCR gene family. View full text Figures at a glance * Figure 1: Effects of GRM3 alterations on cell growth and MEK phosphorylation. () Somatic alterations in GRM3 cause increased proliferation in reduced serum. We seeded A375 pooled GRM3 clones expressing wild-type, p.Gly561Glu, p.Ser610Leu, p.Glu767Lys, p.Glu870Lys or vector alone in 96-well plates in the presence of reduced serum (1% FBS). We harvested the plates and analyzed them by SYBR Green I on a BMG Labtech FluorOptima. Error bars, standard deviation (s.d.). () Mutant GRM3 shows anchorage-independent growth. We seeded Mel-STR cells in a top plug of agar and allowed them to incubate for 2 weeks before analysis by light microscopy and counting using US National Institutes of Health (NIH) ImageJ software (see URLs). Error bars, s.d. n = 3. Students t-tests in all instances showed a *P < 0.05, except for in the test of vector versus wild type. () Mutant GRM3 activates MEK1/2 upon DCG-IV stimulation in Mel-STR and A375 cells. We serum starved Mel-STR pooled GRM3 clones seeded in 6-well dishes for 4 h before the addition of either 2.5 μM DCG-IV or veh! icle for 10 min. After lysis of the cells, we analyzed the lysates on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) gels and immunoblotted them with corresponding antibodies. We generated the ratios shown by ImageJ and Microsoft Excel analysis of phosphorylated protein to total protein blots. () Mutant GRM3 activates MEK1/2 upon DCG-IV stimulation in A375 cells. We analyzed A375 pooled GRM3 clones as described in . * Figure 2: GRM3 mutations increase migration in vitro and in vivo. () A375 pooled GRM3 clones in the absence of stimulus migrate as well as those stimulated with the group 2 metabotropic agonist DCG-IV. We seeded A375 clones in Boyden chambers in either the absence of stimulus of, or in the presence of, 2.5 μM DCG-IV and assessed them for their ability to migrate 16 h later. Error bars, s.d. () We analyzed Mel-STR pooled GRM3 clones for migration as described in . We analyzed stained wells using a Zeiss microscope 10× lens and counted them with NIH ImageJ software. Error bars, s.d. n = 3. () We intravenously injected NOD/SCID mice with A375 pooled GRM3 clones expressing the wild-type, p.Gly561Glu, p.Ser610Leu, p.Glu767Lys, p.Glu870Lys or vector alone and examined them after nine weeks. The graph indicates the number of mice that had lung macrometastases (n = 10; P < 0.05, Fisher's exact test). Shown are representative images of lungs from mice injected with the vector, wild type or mutant-expressing A375 clones. * Figure 3: Expression of mutant GRM3 provides cell proliferation and survival signals in melanoma. () Our protein blot analysis shows that expressing GRM3 shRNA decreases endogenous GRM3 levels. We analyzed HEK 293T cells co-transfected with shRNA targeting GRM3 and FLAG-GRM3 by immunoblot. We analyzed the lysates in parallel using anti-GAPDH. (,) Our quantitative RT-PCR (qRT-PCR) analysis shows that GRM3 shRNA decreases endogenous levels of GRM3. Error bars, s.d. n = 3. qRT-PCR analysis of the wild-type GRM3 cell line (34T) () and the mutant (p.Gly561Glu) GRM3 cell line (36T) () using GRM3- or GAPDH-specific primers. (–) Growth curves of representative melanoma cell lines transduced with shRNA. Error bars, s.d. n = 4. (–) Stable knockdown of GRM3 in mutant-GRM3–expressing cells causes decreased migration compared to wild-type–expressing cells. We seeded wild-type GRM3 melanoma cell lines stably transduced (,) or mutant GRM3 melanoma cell lines stably transduced (–) with either empty vector, shRNA #1 or shRNA #3 (GRM3) in Boyden chamber wells in triplicate and i! ncubated them for 16–72 h before analysis. We quantitated the results using a Student's t-test. Error bars, s.d. n = 3. (,) We subcutaneously injected Nu/Nu mice with either 31T or 36T GRM3 clones stably infected with pLKO.1, shRNA #1 or shRNA #3 against endogeneous GRM3 or 31T (wild-type GRM3) or 63T (p.Glu573Lys) GRM3 clones stably infected with the doxycycline-inducible TRIPz NC, sh639 or sh742 shRNA against endogenous GRM3. Graphs show volumetric measurements of 31T (), 36T GRM3 (constitutive knockdown clones) (), 31T (doxycycline-inducible clones) () or 63T GRM3 (doxycycline-inducible clones) () tumor-bearing mice. We performed all in vivo studies from n = 6 mice. Error bars, s.d. * Figure 4: Melanoma cell lines expressing GRM3 mutants show increased sensitivity to inhibition of MEK by AZD-6244. () Immunoblot analysis of representative melanoma cell lines harboring either wild-type or mutant GRM3. We treated the cells with the indicated concentration of AZD-6244 and analyzed them for ERK1/2 activation. We treated cells for 1 h with AZD-6244 or vehicle alone as a control. We subjected the lysates to protein blot analysis with anti-ERK1/2 (α-ERK1/2), anti–P-ERK1/2 (α-P-ERK1/2) and anti-GAPDH as a loading controls. () Representative dose-response curves showing the efficacy of AZD-6244 against GRM3 mutant lines compared to wild-type GRM3 lines. The relative cell numbers after we treated the cells for 72 h with increasing concentrations (0.002–30 μM) of AZD-6244, as estimated by CellTiter-Glo and plotted as percent survival, as compared to vehicle-treated control, versus log [AZD-6244] concentration in nM (where 1 is 10 nM AZD-6244). We generated fitted lines using four-parameter nonlinear regression. Error bars, s.d. n = 3. () FACS analysis of wild-type (2T) and! p.Ser154Phe, p.Asp280Asn, p.Arg352Trp or p.Glu870Lys mutant (68T) cells showing the cell-cycle distribution (propidium iodide staining; x axis) versus cell count (y axis). Shown are representative plots. () Quantification of FACS-sorted AZD-6244–treated cells. We determined the percentage of apoptotic cells based on the subG1 population for vehicle-treated cells or AZD-6244–treated cells. Error bars, s.d. () Immunoblot analysis of representative melanoma lines expressing wild-type or mutant GRM3 after AZD-6244 treatment using the indicated antibodies to assess PARP cleavage. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions GenBank * SRA024490 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Todd D Prickett, * Xiaomu Wei & * Isabel Cardenas-Navia Affiliations * Cancer Genetics Branch, National Human Genome Research Institute, US National Institutes of Health (NIH), Bethesda, Maryland, USA. * Todd D Prickett, * Xiaomu Wei, * Isabel Cardenas-Navia, * Vijay Walia, * Jared Gartner, * Jiji Jiang & * Yardena Samuels * Genome Technology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA. * Jamie K Teer, * Praveen F Cherukuri & * Elliott H Margulies * Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA. * Jamie K Teer * Ludwig Center for Cancer Genetics and Therapeutics, and Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, USA. * Jimmy C Lin * Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland, USA. * Alfredo Molinolo * Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. * Michael A Davies * Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. * Michael A Davies & * Katherine Stemke-Hale * Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. * Jeffrey E Gershenwald * Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. * Jeffrey E Gershenwald * The Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA. * Steven A Rosenberg Contributions T.D.P., I.C.-N., X.W., E.H.M. and Y.S. designed the study. K.S.-H., M.A.D., J.E.G. and S.A.R. collected and analyzed the melanoma samples. X.W., I.C.-N., J.K.T., J.G., P.F.C. and J.C.L. analyzed the genetic data. T.D.P., A.M., J.J. and V.W. produced and analyzed the functional data. All authors contributed to the final version of the paper. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Yardena Samuels Author Details * Todd D Prickett Search for this author in: * NPG journals * PubMed * Google Scholar * Xiaomu Wei Search for this author in: * NPG journals * PubMed * Google Scholar * Isabel Cardenas-Navia Search for this author in: * NPG journals * PubMed * Google Scholar * Jamie K Teer Search for this author in: * NPG journals * PubMed * Google Scholar * Jimmy C Lin Search for this author in: * NPG journals * PubMed * Google Scholar * Vijay Walia Search for this author in: * NPG journals * PubMed * Google Scholar * Jared Gartner Search for this author in: * NPG journals * PubMed * Google Scholar * Jiji Jiang Search for this author in: * NPG journals * PubMed * Google Scholar * Praveen F Cherukuri Search for this author in: * NPG journals * PubMed * Google Scholar * Alfredo Molinolo Search for this author in: * NPG journals * PubMed * Google Scholar * Michael A Davies Search for this author in: * NPG journals * PubMed * Google Scholar * Jeffrey E Gershenwald Search for this author in: * NPG journals * PubMed * Google Scholar * Katherine Stemke-Hale Search for this author in: * NPG journals * PubMed * Google Scholar * Steven A Rosenberg Search for this author in: * NPG journals * PubMed * Google Scholar * Elliott H Margulies Search for this author in: * NPG journals * PubMed * Google Scholar * Yardena Samuels Contact Yardena Samuels Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (2M) Supplementary Figures 1–6, 8 and 9, Supplementary Tables 1–11 and Supplementary Note. Excel files * Supplementary Table 7 (1M) MIP probes used for GPCR capture Additional data
• Identification of low-frequency variants associated with gout and serum uric acid levels
  - Nat Genet 43(11):1127-1130 (2011)
  Nature Genetics | Letter Identification of low-frequency variants associated with gout and serum uric acid levels * Patrick Sulem1, 13 * Daniel F Gudbjartsson1, 13 * G Bragi Walters1, 13 * Hafdis T Helgadottir1 * Agnar Helgason1 * Sigurjon A Gudjonsson1 * Carlo Zanon1 * Soren Besenbacher1 * Gyda Bjornsdottir1 * Olafur T Magnusson1 * Gisli Magnusson1 * Eirikur Hjartarson1 * Jona Saemundsdottir1 * Arnaldur Gylfason1 * Adalbjorg Jonasdottir1 * Hilma Holm1 * Ari Karason1 * Thorunn Rafnar1 * Hreinn Stefansson1 * Ole A Andreassen2 * Jesper H Pedersen3 * Allan I Pack4 * Marieke C H de Visser5 * Lambertus A Kiemeney5, 6, 7 * Arni J Geirsson8 * Gudmundur I Eyjolfsson9 * Isleifur Olafsson10 * Augustine Kong1 * Gisli Masson1 * Helgi Jonsson8, 11 * Unnur Thorsteinsdottir1, 11 * Ingileif Jonsdottir1, 11, 12 * Kari Stefansson1, 11 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:1127–1130Year published:(2011)DOI:doi:10.1038/ng.972Received10 May 2011Accepted16 September 2011Published online09 October 2011 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg We tested 16 million SNPs, identified through whole-genome sequencing of 457 Icelanders, for association with gout and serum uric acid levels. Genotypes were imputed into 41,675 chip-genotyped Icelanders and their relatives, for effective sample sizes of 968 individuals with gout and 15,506 individuals for whom serum uric acid measurements were available. We identified a low-frequency missense variant (c.1580C>G) in ALDH16A1 associated with gout (OR = 3.12, P = 1.5 × 10−16, at-risk allele frequency = 0.019) and serum uric acid levels (effect = 0.36 s.d., P = 4.5 × 10−21). We confirmed the association with gout by performing Sanger sequencing on 6,017 Icelanders. The association with gout was stronger in males relative to females. We also found a second variant on chromosome 1 associated with gout (OR = 1.92, P = 0.046, at-risk allele frequency = 0.986) and serum uric acid levels (effect = 0.48 s.d., P = 4.5 × 10−16). This variant is close to a common variant previou! sly associated with serum uric acid levels. This work illustrates how whole-genome sequencing data allow the detection of associations between low-frequency variants and complex traits. View full text Figures at a glance * Figure 1: Overview of the chromosome 1 centromeric and chromosome 19q13 loci. () The 1p pericentromeric region. () The 1q pericentromeric region. () The 19q13 locus. The black circles and orange crosses indicate −log10P values for the association of SNPs imputed based on genome-wide sequencing with serum uric acid levels and gout, respectively, as a function of their build 36 coordinates. The purple Xs show −log10P values for gout, conditional on the effect of the strongest SNP at each locus. Neighboring genes are shown in blue. Recombination rates are reported in centimorgans per megabase (cM/Mb). * Figure 2: Effects on gout and serum uric acid levels of newly discovered and previously reported sequence variants stratified by sex. Male and female effects are displayed in blue and red, respectively. For clarity, the male and female effects for each locus are linked by a black line. The serum uric acid effect is given in s.d. The horizontal and vertical bars represent one standard error for the serum uric acid effect and gout OR, respectively. The four strongest loci are labeled. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions Entrez Nucleotide * NM_001145396 GenBank * NM_153329 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Patrick Sulem, * Daniel F Gudbjartsson & * G Bragi Walters Affiliations * deCODE genetics, Reykjavik, Iceland. * Patrick Sulem, * Daniel F Gudbjartsson, * G Bragi Walters, * Hafdis T Helgadottir, * Agnar Helgason, * Sigurjon A Gudjonsson, * Carlo Zanon, * Soren Besenbacher, * Gyda Bjornsdottir, * Olafur T Magnusson, * Gisli Magnusson, * Eirikur Hjartarson, * Jona Saemundsdottir, * Arnaldur Gylfason, * Adalbjorg Jonasdottir, * Hilma Holm, * Ari Karason, * Thorunn Rafnar, * Hreinn Stefansson, * Augustine Kong, * Gisli Masson, * Unnur Thorsteinsdottir, * Ingileif Jonsdottir & * Kari Stefansson * Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway. * Ole A Andreassen * Department of Cardiothoracic Surgery, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. * Jesper H Pedersen * Center for Sleep and Circardian Neurobiology, Division of Sleep Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. * Allan I Pack * Department of Epidemiology, Biostatistics & Health Technology Assessment, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Marieke C H de Visser & * Lambertus A Kiemeney * Comprehensive Cancer Center East (IKO), Nijmegen, The Netherlands. * Lambertus A Kiemeney * Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Lambertus A Kiemeney * Landspitali, The National University Hospital of Iceland, Department of Medicine, Reykjavik, Iceland. * Arni J Geirsson & * Helgi Jonsson * Icelandic Medical Center (Laeknasetrid) Laboratory in Mjodd (RAM), Reykjavik, Iceland. * Gudmundur I Eyjolfsson * Landspitali, The National University Hospital of Iceland, Department of Clinical Biochemistry, Reykjavik, Iceland. * Isleifur Olafsson * University of Iceland, Faculty of Medicine, Reykjavik, Iceland. * Helgi Jonsson, * Unnur Thorsteinsdottir, * Ingileif Jonsdottir & * Kari Stefansson * Landspitali, The National University Hospital of Iceland, Department of Immunology, Reykjavik, Iceland. * Ingileif Jonsdottir Contributions P.S., D.F.G., G.B.W., H.J., U.T., I.J. and K.S. wrote the manuscript. P.S., D.F.G., G.B.W., G.B., H.H., H.J., U.T., I.J. and K.S. designed the study. A. Karason, T.R., H.S., O.A.A., J.H.P., A.I.P., M.C.H.d.V., L.A.K., A.J.G., G.I.E., I.O., H.J. and I.J. recruited participants for the study and collected clinical or paraclinical information. P.S., D.F.G., G.B.W., A.H., S.B., A.G., A. Kong and G. Masson performed statistical analyses. S.A.G. and C.Z. performed bioinformatics analyses. O.T.M., G. Magnusson, E.H., J.S., A.J. and G. Masson generated, processed and managed data for the whole-genome sequencing project. H.T.H. performed genotype and sequence calling. Competing financial interests Some of the authors employed by deCODE genetics own stock or stock options in the company. Corresponding authors Correspondence to: * Patrick Sulem or * Kari Stefansson Author Details * Patrick Sulem Contact Patrick Sulem Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel F Gudbjartsson Search for this author in: * NPG journals * PubMed * Google Scholar * G Bragi Walters Search for this author in: * NPG journals * PubMed * Google Scholar * Hafdis T Helgadottir Search for this author in: * NPG journals * PubMed * Google Scholar * Agnar Helgason Search for this author in: * NPG journals * PubMed * Google Scholar * Sigurjon A Gudjonsson Search for this author in: * NPG journals * PubMed * Google Scholar * Carlo Zanon Search for this author in: * NPG journals * PubMed * Google Scholar * Soren Besenbacher Search for this author in: * NPG journals * PubMed * Google Scholar * Gyda Bjornsdottir Search for this author in: * NPG journals * PubMed * Google Scholar * Olafur T Magnusson Search for this author in: * NPG journals * PubMed * Google Scholar * Gisli Magnusson Search for this author in: * NPG journals * PubMed * Google Scholar * Eirikur Hjartarson Search for this author in: * NPG journals * PubMed * Google Scholar * Jona Saemundsdottir Search for this author in: * NPG journals * PubMed * Google Scholar * Arnaldur Gylfason Search for this author in: * NPG journals * PubMed * Google Scholar * Adalbjorg Jonasdottir Search for this author in: * NPG journals * PubMed * Google Scholar * Hilma Holm Search for this author in: * NPG journals * PubMed * Google Scholar * Ari Karason Search for this author in: * NPG journals * PubMed * Google Scholar * Thorunn Rafnar Search for this author in: * NPG journals * PubMed * Google Scholar * Hreinn Stefansson Search for this author in: * NPG journals * PubMed * Google Scholar * Ole A Andreassen Search for this author in: * NPG journals * PubMed * Google Scholar * Jesper H Pedersen Search for this author in: * NPG journals * PubMed * Google Scholar * Allan I Pack Search for this author in: * NPG journals * PubMed * Google Scholar * Marieke C H de Visser Search for this author in: * NPG journals * PubMed * Google Scholar * Lambertus A Kiemeney Search for this author in: * NPG journals * PubMed * Google Scholar * Arni J Geirsson Search for this author in: * NPG journals * PubMed * Google Scholar * Gudmundur I Eyjolfsson Search for this author in: * NPG journals * PubMed * Google Scholar * Isleifur Olafsson Search for this author in: * NPG journals * PubMed * Google Scholar * Augustine Kong Search for this author in: * NPG journals * PubMed * Google Scholar * Gisli Masson Search for this author in: * NPG journals * PubMed * Google Scholar * Helgi Jonsson Search for this author in: * NPG journals * PubMed * Google Scholar * Unnur Thorsteinsdottir Search for this author in: * NPG journals * PubMed * Google Scholar * Ingileif Jonsdottir Search for this author in: * NPG journals * PubMed * Google Scholar * Kari Stefansson Contact Kari Stefansson Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (1M) Supplementary Note, Supplementary Tables 1–6 and Supplementary Figures 1–3 Additional data
• Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma
  - Nat Genet 43(11):1131-1138 (2011)
  Nature Genetics | Letter Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma * John C Chambers1, 2, 3, 113 * Weihua Zhang1, 3, 113 * Joban Sehmi3, 4, 113 * Xinzhong Li5, 113 * Mark N Wass6, 113 * Pim Van der Harst7, 113 * Hilma Holm8, 113 * Serena Sanna9, 113 * Maryam Kavousi10, 11, 113 * Sebastian E Baumeister12 * Lachlan J Coin1 * Guohong Deng13 * Christian Gieger14 * Nancy L Heard-Costa15 * Jouke-Jan Hottenga16 * Brigitte Kühnel14 * Vinod Kumar17 * Vasiliki Lagou18, 19, 20 * Liming Liang21, 22 * Jian'an Luan23 * Pedro Marques Vidal24 * Irene Mateo Leach7 * Paul F O'Reilly1 * John F Peden25 * Nilufer Rahmioglu19 * Pasi Soininen26, 27 * Elizabeth K Speliotes28, 29 * Xin Yuan30 * Gudmar Thorleifsson8 * Behrooz Z Alizadeh18 * Larry D Atwood31 * Ingrid B Borecki32 * Morris J Brown33 * Pimphen Charoen1, 34 * Francesco Cucca9 * Debashish Das3 * Eco J C de Geus16, 35 * Anna L Dixon36 * Angela Döring37 * Georg Ehret38, 39, 40 * Gudmundur I Eyjolfsson41 * Martin Farrall25, 42 * Nita G Forouhi23 * Nele Friedrich43 * Wolfram Goessling44, 45, 46 * Daniel F Gudbjartsson8 * Tamara B Harris47 * Anna-Liisa Hartikainen48 * Simon Heath49 * Gideon M Hirschfield50, 51, 52 * Albert Hofman10, 11 * Georg Homuth53 * Elina Hyppönen54 * Harry L A Janssen10, 55 * Toby Johnson56 * Antti J Kangas26 * Ido P Kema57 * Jens P Kühn58 * Sandra Lai9 * Mark Lathrop49, 59 * Markus M Lerch60 * Yun Li61 * T Jake Liang62 * Jing-Ping Lin63 * Ruth J F Loos23 * Nicholas G Martin64 * Miriam F Moffatt36 * Grant W Montgomery64 * Patricia B Munroe56 * Kiran Musunuru31, 65, 66, 67, 68 * Yusuke Nakamura17 * Christopher J O'Donnell69 * Isleifur Olafsson70 * Brenda W Penninx71, 72, 73 * Anneli Pouta48, 74 * Bram P Prins18 * Inga Prokopenko19, 20 * Ralf Puls58 * Aimo Ruokonen75 * Markku J Savolainen26, 76 * David Schlessinger77 * Jeoffrey N L Schouten55 * Udo Seedorf78 * Srijita Sen-Chowdhry1 * Katherine A Siminovitch50, 79, 80, 81, 82 * Johannes H Smit71 * Timothy D Spector83 * Wenting Tan13 * Tanya M Teslovich84 * Taru Tukiainen1, 26 * Andre G Uitterlinden10, 11, 85 * Melanie M Van der Klauw86, 87 * Ramachandran S Vasan88, 89 * Chris Wallace33 * Henri Wallaschofski43 * H-Erich Wichmann37, 90, 91 * Gonneke Willemsen16, 92 * Peter Würtz1, 26 * Chun Xu93 * Laura M Yerges-Armstrong94 * Alcohol Genome-wide Association (AlcGen) Consortium * Diabetes Genetics Replication and Meta-analyses (DIAGRAM+) Study * Genetic Investigation of Anthropometric Traits (GIANT) Consortium * Global Lipids Genetics Consortium * Genetics of Liver Disease (GOLD) Consortium * International Consortium for Blood Pressure (ICBP-GWAS) * Meta-analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) * Goncalo R Abecasis84 * Kourosh R Ahmadi83 * Dorret I Boomsma16, 92 * Mark Caulfield56 * William O Cookson36 * Cornelia M van Duijn10, 11, 96 * Philippe Froguel97 * Koichi Matsuda17 * Mark I McCarthy19, 20, 98 * Christa Meisinger99 * Vincent Mooser30 * Kirsi H Pietiläinen100, 101, 102 * Gunter Schumann103 * Harold Snieder18 * Michael J E Sternberg6, 87 * Ronald P Stolk104 * Howard C Thomas2, 105 * Unnur Thorsteinsdottir8, 106 * Manuela Uda9 * Gérard Waeber107 * Nicholas J Wareham23 * Dawn M Waterworth30 * Hugh Watkins25, 42 * John B Whitfield64 * Jacqueline C M Witteman10, 11 * Bruce H R Wolffenbuttel86, 87 * Caroline S Fox69, 108 * Mika Ala-Korpela26, 27, 76, 113 * Kari Stefansson8, 106, 113 * Peter Vollenweider107, 113 * Henry Völzke12, 113 * Eric E Schadt109, 113 * James Scott4, 113 * Marjo-Riitta Järvelin1, 74, 110, 111, 112, 113 * Paul Elliott1, 112, 113 * Jaspal S Kooner2, 3, 4, 113 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:1131–1138Year published:(2011)DOI:doi:10.1038/ng.970Received08 March 2011Accepted12 September 2011Published online16 October 2011 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10−8 to P = 10−190). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1! , EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function. View full text Figures at a glance * Figure 1: Summary of study design. * Figure 2: Manhattan plots of association of SNPs with ALT, ALP and GGT in the GWAS. SNPs reaching genome-wide significance (P < 1 × 10−8) are red; SNPs with P > 1 × 10−8 and P < 1 × 10−7 are green. * Figure 3: Association of FADS1, FADS2, GCKR, HNF1A, TRIB1 and PPP1R3B loci with NMR metabonome. Bars are for –log10P value, signed for direction of effect. Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * John C Chambers, * Weihua Zhang, * Joban Sehmi, * Xinzhong Li, * Mark N Wass, * Pim Van der Harst, * Hilma Holm, * Serena Sanna, * Maryam Kavousi, * Mika Ala-Korpela, * Kari Stefansson, * Peter Vollenweider, * Henry Völzke, * Eric E Schadt, * James Scott, * Marjo-Riitta Järvelin, * Paul Elliott & * Jaspal S Kooner Affiliations * Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, UK. * John C Chambers, * Weihua Zhang, * Lachlan J Coin, * Paul F O'Reilly, * Pimphen Charoen, * Srijita Sen-Chowdhry, * Taru Tukiainen, * Peter Würtz, * Marjo-Riitta Järvelin & * Paul Elliott * Imperial College Healthcare National Health Service (NHS) Trust, London, UK. * John C Chambers, * Howard C Thomas & * Jaspal S Kooner * Ealing Hospital NHS Trust, Middlesex, UK. * John C Chambers, * Weihua Zhang, * Joban Sehmi, * Debashish Das & * Jaspal S Kooner * National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, UK. * Joban Sehmi, * James Scott & * Jaspal S Kooner * Institute of Clinical Science, Imperial College London, Royal Brompton Hospital, London, UK. * Xinzhong Li * Structural Bioinformatics Group, Division of Molecular Biosciences, Imperial College London, South Kensington, London, UK. * Mark N Wass & * Michael J E Sternberg * Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands. * Pim Van der Harst & * Irene Mateo Leach * deCODE genetics, Reykjavik, Iceland. * Hilma Holm, * Gudmar Thorleifsson, * Daniel F Gudbjartsson, * Unnur Thorsteinsdottir & * Kari Stefansson * Istituto di Ricerca Genetica e Biomedica del Consiglio Nazionale delle Ricerche, Monserrato, Cagliari, Italy. * Serena Sanna, * Francesco Cucca, * Sandra Lai & * Manuela Uda * Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands. * Maryam Kavousi, * Albert Hofman, * Harry L A Janssen, * Andre G Uitterlinden, * Cornelia M van Duijn & * Jacqueline C M Witteman * Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Health Aging, Rotterdam, The Netherlands. * Maryam Kavousi, * Albert Hofman, * Andre G Uitterlinden, * Cornelia M van Duijn & * Jacqueline C M Witteman * Institute for Community Medicine, University of Greifswald, Germany. * Sebastian E Baumeister & * Henry Völzke * Institute of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China. * Guohong Deng & * Wenting Tan * Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. * Christian Gieger & * Brigitte Kühnel * Department of Neurology, Boston University School of Medicine, Boston Massachusetts, USA. * Nancy L Heard-Costa * Department of Biological Psychology, VU University Amsterdam (VUA), Amsterdam, The Netherlands. * Jouke-Jan Hottenga, * Eco J C de Geus, * Gonneke Willemsen & * Dorret I Boomsma * Laboratory of Molecular Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. * Vinod Kumar, * Yusuke Nakamura & * Koichi Matsuda * Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. * Vasiliki Lagou, * Behrooz Z Alizadeh, * Bram P Prins & * Harold Snieder * Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, UK. * Vasiliki Lagou, * Nilufer Rahmioglu, * Inga Prokopenko & * Mark I McCarthy * Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK. * Vasiliki Lagou, * Inga Prokopenko & * Mark I McCarthy * Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. * Liming Liang * Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA. * Liming Liang * Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Addenbrooke′s Hospital, Cambridge UK. * Jian'an Luan, * Nita G Forouhi, * Ruth J F Loos & * Nicholas J Wareham * Institute of Social and Preventive Medicine (IUMSP), University Hospital and University of Lausanne, Lausanne, Switzerland. * Pedro Marques Vidal * Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. * John F Peden, * Martin Farrall & * Hugh Watkins * Computational Medicine Research Group, Institute of Clinical Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland. * Pasi Soininen, * Antti J Kangas, * Markku J Savolainen, * Taru Tukiainen, * Peter Würtz & * Mika Ala-Korpela * Nuclear Magnetic Resonance (NMR) Metabonomics Laboratory, Department of Biosciences, University of Eastern Finland, Kuopio, Finland. * Pasi Soininen & * Mika Ala-Korpela * Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA. * Elizabeth K Speliotes * Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA. * Elizabeth K Speliotes * Genetics, GlaxoSmithKline, King of Prussia, Pennsylvania, USA. * Xin Yuan, * Vincent Mooser & * Dawn M Waterworth * Boston University School of Medicine, Boston, Massachusetts, USA. * Larry D Atwood & * Kiran Musunuru * Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, Saint Louis, Missouri, USA. * Ingrid B Borecki * The Diabetes Inflammation Laboratory, Cambridge Institute of Medical Research, University of Cambridge, Cambridge, UK. * Morris J Brown & * Chris Wallace * Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. * Pimphen Charoen * Neuroscience Campus Amsterdam, VUA and VUA Medical Center, Amsterdam, The Netherlands. * Eco J C de Geus * National Heart and Lung Institute, Imperial College London, London, UK. * Anna L Dixon, * Miriam F Moffatt & * William O Cookson * Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. * Angela Döring & * H-Erich Wichmann * Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. * Georg Ehret * IUMSP, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland. * Georg Ehret * Cardiology, Department of Medicine, Geneva University Hospital, Geneva, Switzerland. * Georg Ehret * The Laboratory in Mjodd, Reykjavik, Iceland. * Gudmundur I Eyjolfsson * Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK. * Martin Farrall & * Hugh Watkins * Institute of Clinical Chemistry and Laboratory Medicine, University of Greifswald, Germany. * Nele Friedrich & * Henri Wallaschofski * Genetics and Gastroenterology Divisions, Brigham and Women′s Hospital, Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. * Wolfram Goessling * Harvard Medical School, Boston, Massachusetts, USA. * Wolfram Goessling * Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. * Wolfram Goessling * Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, US National Institutes of Health (NIH), Bethesda, Maryland, USA. * Tamara B Harris * Institute of Clinical Medicine, University of Oulu, Oulu, Finland. * Anna-Liisa Hartikainen & * Anneli Pouta * CEA-IG Centre National de Genotypage, Evry Cedex, France. * Simon Heath & * Mark Lathrop * Department of Medicine, University of Toronto, Toronto, Ontario, Canada. * Gideon M Hirschfield & * Katherine A Siminovitch * Liver Center, Toronto Western Hospital, Toronto, Ontario, Canada. * Gideon M Hirschfield * Centre for Liver Research, University of Birmingham, Birmingham, UK. * Gideon M Hirschfield * Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany. * Georg Homuth * Centre for Paediatric Epidemiology and Biostatistics, Institute of Child Health, London, UK. * Elina Hyppönen * Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands. * Harry L A Janssen & * Jeoffrey N L Schouten * Clinical Pharmacology and The Genome Center, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. * Toby Johnson, * Patricia B Munroe & * Mark Caulfield * Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. * Ido P Kema * Institute of Diagnostic Radiology and Neuroradiology, University of Greifswald, Greifswald, Germany. * Jens P Kühn & * Ralf Puls * Fondation Jean Dausset Ceph, Paris, France. * Mark Lathrop * Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. * Markus M Lerch * Department of Genetics, Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA. * Yun Li * Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA. * T Jake Liang * Office of Biostatistics Research, Division of Cardiovascular Sciences, National Heart, Lung and Blood Institute (NHLBI), NIH, Bethesda, Maryland, USA. * Jing-Ping Lin * Queensland Institute of Medical Research, Brisbane, Queensland, Australia. * Nicholas G Martin, * Grant W Montgomery & * John B Whitfield * Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. * Kiran Musunuru * Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. * Kiran Musunuru * Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. * Kiran Musunuru * Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. * Kiran Musunuru * NHLBI Framingham Heart Study, Framingham, Massachusetts, USA. * Christopher J O'Donnell & * Caroline S Fox * Department of Clinical Biochemistry, Landspitali University Hospital, Reykjavik, Iceland. * Isleifur Olafsson * Department of Psychiatry and EMGO Institute for Health and Care Research, VUA Medical Centre, Amsterdam, The Netherlands. * Brenda W Penninx & * Johannes H Smit * Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands. * Brenda W Penninx * Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. * Brenda W Penninx * Department of Lifecourse and Services, National Institute for Health and Welfare, Oulu, Finland. * Anneli Pouta & * Marjo-Riitta Järvelin * Institute of Diagnostics, Clinical Chemistry, University of Oulu, Oulu, Finland. * Aimo Ruokonen * Department of Internal Medicine and Biocenter Oulu, Clinical Research Center, University of Oulu, Oulu, Finland. * Markku J Savolainen & * Mika Ala-Korpela * Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland, USA. * David Schlessinger * Gesellschaft für Arterioskleroseforschung, Leibniz-Institut für Arterioskleroseforschung an der Universität Münster, Münster, Germany. * Udo Seedorf * Department of Immunology, University of Toronto, Toronto, Ontario, Canada. * Katherine A Siminovitch * Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. * Katherine A Siminovitch * Mount Sinai Hospital Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada. * Katherine A Siminovitch * Toronto General Research Institute, Toronto, Ontario, Canada. * Katherine A Siminovitch * Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. * Timothy D Spector & * Kourosh R Ahmadi * Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA. * Tanya M Teslovich & * Goncalo R Abecasis * Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. * Andre G Uitterlinden * Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. * Melanie M Van der Klauw & * Bruce H R Wolffenbuttel * LifeLines Cohort Study and Biobank, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. * Melanie M Van der Klauw, * Michael J E Sternberg & * Bruce H R Wolffenbuttel * Section of Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, Massachusetts, USA. * Ramachandran S Vasan * Cardiology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA. * Ramachandran S Vasan * Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany. * H-Erich Wichmann * Klinikum Grosshadern, Munich, Germany. * H-Erich Wichmann * EMGO+ Institute, VUA Medical Center, Amsterdam, The Netherlands. * Gonneke Willemsen & * Dorret I Boomsma * Samuel Lunenfeld and Toronto General Research Institutes, Toronto, Ontario, Canada. * Chun Xu * Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA. * Laura M Yerges-Armstrong * Center for Medical Systems Biology, Rotterdam, The Netherlands. * Cornelia M van Duijn * Genomics of Common Diseases, School of Public Health, Imperial College London, Hammersmith Hospital, London, UK. * Philippe Froguel * Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, UK. * Mark I McCarthy * Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. * Christa Meisinger * Obesity Research Unit, Department of Medicine, Division of Internal Medicine, Helsinki University Hospital, Helsinki, Finland. * Kirsi H Pietiläinen * The Institute for Molecular Medicine FIMM, Helsinki, Finland. * Kirsi H Pietiläinen * Hjelt Institute, Department of Public Health, University of Helsinki, Helsinki, Finland. * Kirsi H Pietiläinen * MRC-Social Genetic Developmental Psychiatry (SGDP) Centre, Institute of Psychiatry, King's College, London, UK. * Gunter Schumann * Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. * Ronald P Stolk * Faculty of Medicine, Imperial College London, London, UK. * Howard C Thomas * Faculty of Medicine, University of Iceland, Reykjavik, Iceland. * Unnur Thorsteinsdottir & * Kari Stefansson * Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. * Gérard Waeber & * Peter Vollenweider * Division of Endocrinology, Hypertension, and Metabolism, Brigham and Women's Hospital, Boston, Massachusetts, USA. * Caroline S Fox * Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA. * Eric E Schadt * Institute of Health Sciences, University of Oulu, Oulu, Finland. * Marjo-Riitta Järvelin * Biocenter Oulu, University of Oulu, Oulu, Finland. * Marjo-Riitta Järvelin * MRC–Health Protection Agency (HPA) Centre for Environment and Health, Imperial College London, London, UK. * Marjo-Riitta Järvelin & * Paul Elliott Consortia * Alcohol Genome-wide Association (AlcGen) Consortium * Diabetes Genetics Replication and Meta-analyses (DIAGRAM+) Study * Genetic Investigation of Anthropometric Traits (GIANT) Consortium * Global Lipids Genetics Consortium * Genetics of Liver Disease (GOLD) Consortium * International Consortium for Blood Pressure (ICBP-GWAS) * Meta-analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) Contributions Study organization and manuscript preparation was done by J.C.C., W.Z., J. Sehmi, X.L., M.N.W., P.V.d.H., H.H., S.S., M.K., M.A.-K., K.S., P.V., H.V., E.E.S., J. Scott, M.-R.J., P.E. and J.S.K. All authors reviewed and had the opportunity to comment on the manuscript. Data collection and analysis in the participating GWASs were done by G.W.M., J.B.W. and N.G.M. (Australian Twin Cohort); C.W., M.C., M.J.B. and P.B.M. (BRIGHT); D.M.W., G. Waeber, P.M.V., P.V., V.M. and X.Y. (CoLaus); D.F.G., G.I.E., G.T., H.H., I.O., K.S. and U.T. (deCODE); J.L., N.G.F., N.J.W. and R.J.F.L. (Fenland); K.H.P. (Finnish Twin Cohort); C.J.O., C.S.F., J.P.L., L.D.A., N.L.H.-C., R.S.V., T.J.L. and W.G. (Framingham Heart Study); A.D., B.K., C.G., C.M. and H.-E.W. (KORA); B.H.R.W., I.M.L., I.P.K., M.M.V.d.K., P.V.d.H. and R.P.S. (LIFELINES); D.D., G.D., H.C.T., I.P., J.C.C., J. Scott, J. Sehmi, J.S.K., M.I.M., P.E., P.F., S.S.-C., W.Z., X.L. and Y.L. (LOLIPOP); B.P.P., B.W.P., B.Z.A., H.S., J.H.S. and! V.L. (NESDA); D.I.B., E.J.C.d.G., G. Willemsen, J.-J.H. (Netherlands Twins Register); A.-L.H., A.P., A.R., E.H., M.-R.J. and P.F.O. (Northern Finland Birth Cohort 1966); H. Watkins, J.F.P., M.F. and U.S. (PROCARDIS); A.G.U., A.H., C.M.v.D., H.L.A.J., J.C.M.W., J.N.L.S. and M.K. (Rotterdam Study 1); D.S., F.C., G.R.A., M.U., S.L. and S.S. (SardiNIA); G.H., H.V., H. Wallaschofski, J.P.K., M.M.L., N.F., R.P. and S.E.B. (SHIP); K.R.A., N.R. and T.D.S. (TwinsUK). Biologic associations of loci and bioinformatics were carried out by G.D., W.T., K. Matsuda, V.K., Y.N. and by G.S., L.J.C., P.C. (AlcGen Consortium), C.X., G.M.H., K.A.S. (Canadian Primary Biliary Cirrhosis Consortium), K. Musunuru, T.M.T. (Global Lipids Consortium), E.K.S., I.B.B., L.M.Y.A., T.B.H. (GOLD consortium) and G.E. and T.J. (ICBP-GWAS). Gene expression analyses were done by E.E.S., A.L.D., H.H., G.T., L.L., M.F.M., M.L., S.H. and W.O.C. Metabonomic analyses were done by A.J.K., M.A.-K., M.J.S., P.S., P.W. a! nd T.T. Structural biology was done by M.J.E.S. and M.N.W. A full list of members is given in Supplementary Note. Alcohol Genome-wide Association (AlcGen) Consortium Diabetes Genetics Replication and Meta-analyses (DIAGRAM+) Study Genetic Investigation of Anthropometric Traits (GIANT) Consortium Global Lipids Genetics Consortium Genetics of Liver Disease (GOLD) Consortium International Consortium for Blood Pressure (ICBP-GWAS) Meta-analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * John C Chambers or * Paul Elliott or * Jaspal S Kooner Author Details * John C Chambers Contact John C Chambers Search for this author in: * NPG journals * PubMed * Google Scholar * Weihua Zhang Search for this author in: * NPG journals * PubMed * Google Scholar * Joban Sehmi Search for this author in: * NPG journals * PubMed * Google Scholar * Xinzhong Li Search for this author in: * NPG journals * PubMed * Google Scholar * Mark N Wass Search for this author in: * NPG journals * PubMed * Google Scholar * Pim Van der Harst Search for this author in: * NPG journals * PubMed * Google Scholar * Hilma Holm Search for this author in: * NPG journals * PubMed * Google Scholar * Serena Sanna Search for this author in: * NPG journals * PubMed * Google Scholar * Maryam Kavousi Search for this author in: * NPG journals * PubMed * Google Scholar * Sebastian E Baumeister Search for this author in: * NPG journals * PubMed * Google Scholar * Lachlan J Coin 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• Genome-wide association study identifies susceptibility loci for dengue shock syndrome at MICB and PLCE1
  - Nat Genet 43(11):1139-1141 (2011)
  Nature Genetics | Letter Genome-wide association study identifies susceptibility loci for dengue shock syndrome at MICB and PLCE1 * Chiea Chuen Khor1, 2, 3 * Tran Nguyen Bich Chau4 * Junxiong Pang1, 5 * Sonia Davila2, 6 * Hoang Truong Long1, 4 * Rick T H Ong2 * Sarah J Dunstan4, 7 * Bridget Wills4, 7 * Jeremy Farrar4, 7 * Ta Van Tram8 * Tran Thi Gan8 * Nguyen Thi Nguyet Binh9 * Le Trung Tri9 * Le Bich Lien10 * Nguyen Minh Tuan10 * Nguyen Thi Hong Tham11 * Mai Ngoc Lanh11 * Nguyen Minh Nguyet4 * Nguyen Trong Hieu12 * Nguyen Van N Vinh Chau13 * Tran Thi Thuy14 * Dennis E K Tan6 * Anavaj Sakuntabhai15, 16 * Yik-Ying Teo5, 6, 17 * Martin L Hibberd1, 5, 18 * Cameron P Simmons4, 7, 18 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:1139–1141Year published:(2011)DOI:doi:10.1038/ng.960Received24 May 2011Accepted09 September 2011Published online16 October 2011 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Hypovolemic shock (dengue shock syndrome (DSS)) is the most common life-threatening complication of dengue. We conducted a genome-wide association study of 2,008 pediatric cases treated for DSS and 2,018 controls from Vietnam. Replication of the most significantly associated markers was carried out in an independent Vietnamese sample of 1,737 cases and 2,934 controls. SNPs at two loci showed genome-wide significant association with DSS. We identified a susceptibility locus at MICB (major histocompatibility complex (MHC) class I polypeptide-related sequence B), which was within the broad MHC region on chromosome 6 but outside the class I and class II HLA loci (rs3132468, Pmeta = 4.41 × 10−11, per-allele odds ratio (OR) = 1.34 (95% confidence interval: 1.23–1.46)). We identified associated variants within PLCE1 (phospholipase C, epsilon 1) on chromosome 10 (rs3765524, Pmeta = 3.08 × 10−10, per-allele OR = 0.80 (95% confidence interval: 0.75–0.86)). We identify two lo! ci associated with susceptibility to DSS in people with dengue, suggesting possible mechanisms for this severe complication of dengue. View full text Accession codes * Accession codes * Author information * Supplementary information Referenced accessions Entrez Nucleotide * NM_005931 * NM_016341 * NM_001165979 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Martin L Hibberd & * Cameron P Simmons Affiliations * Infectious Diseases, Genome Institute of Singapore, Singapore. * Chiea Chuen Khor, * Junxiong Pang, * Hoang Truong Long & * Martin L Hibberd * Genome Institute of Singapore–National University of Singapore Centre for Molecular Epidemiology, National University of Singapore, Singapore. * Chiea Chuen Khor, * Sonia Davila & * Rick T H Ong * Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. * Chiea Chuen Khor * Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam. * Tran Nguyen Bich Chau, * Hoang Truong Long, * Sarah J Dunstan, * Bridget Wills, * Jeremy Farrar, * Nguyen Minh Nguyet & * Cameron P Simmons * Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. * Junxiong Pang, * Yik-Ying Teo & * Martin L Hibberd * Human Genetics, Genome Institute of Singapore, Singapore. * Sonia Davila, * Dennis E K Tan & * Yik-Ying Teo * Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK. * Sarah J Dunstan, * Bridget Wills, * Jeremy Farrar & * Cameron P Simmons * Tien Giang Hospital, My Tho City, Tien Giang Province, Vietnam. * Ta Van Tram & * Tran Thi Gan * Sa Dec Hospital, Sa Dec Town, Dong Thap Province, Vietnam. * Nguyen Thi Nguyet Binh & * Le Trung Tri * Department of Dengue Hemorrhagic Fever, Children's Hospital No. 1, Ho Chi Minh City, Vietnam. * Le Bich Lien & * Nguyen Minh Tuan * Dong Thap Hospital, Cao Lanh City, Dong Thap Province, Vietnam. * Nguyen Thi Hong Tham & * Mai Ngoc Lanh * Hung Vuong Hospital, District 5, Ho Chi Minh City, Vietnam. * Nguyen Trong Hieu * Hospital for Tropical Diseases, District 5, Ho Chi Minh City, Vietnam. * Nguyen Van N Vinh Chau * Department of Infectious Diseases, Children's Hospital No. 2, District 1, Ho Chi Minh City, Vietnam. * Tran Thi Thuy * Institut Pasteur, Laboratoire de la Génétique de la réponse aux infections chez l'homme, Paris, France. * Anavaj Sakuntabhai * Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. * Anavaj Sakuntabhai * Department of Statistics and Applied Probability, Faculty of Science, National University of Singapore, Singapore. * Yik-Ying Teo Contributions M.L.H. and C.P.S. are the study principal investigators who conceived and obtained funding for the project. C.C.K. organized and supervised the GWAS and replication genotyping pipeline, devised the overall analysis plan and wrote the first draft of the manuscript with input from M.L.H., C.P.S. and S.D. T.N.B.C. is the lead coordinator of clinical samples and phenotypes for both the discovery and replication stages. J.P. and D.E.K.T. performed genotyping and quality checks on all samples. C.C.K., S.D., R.T.H.O. and Y.-Y.T. analyzed the data. H.T.L., S.J.D., B.W., J.F., T.V.T., T.T.G., N.T.N.B., L.T.T., L.B.L., N.M.T., N.T.H.T., M.N.L., N.M.N., N.T.H., N.V.V.C., T.T.T. and A.S. coordinated and contributed patient and database phenotype collections as lead investigators for their respective sample collections. D.E.K.T. and J.P. performed genotyping and DNA quality checks. All authors critically reviewed manuscript revisions and contributed intellectual input to the final submis! sion. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Martin L Hibberd or * Cameron P Simmons Author Details * Chiea Chuen Khor Search for this author in: * NPG journals * PubMed * Google Scholar * Tran Nguyen Bich Chau Search for this author in: * NPG journals * PubMed * Google Scholar * Junxiong Pang Search for this author in: * NPG journals * PubMed * Google Scholar * Sonia Davila Search for this author in: * NPG journals * PubMed * Google Scholar * Hoang Truong Long Search for this author in: * NPG journals * PubMed * Google Scholar * Rick T H Ong Search for this author in: * NPG journals * PubMed * Google Scholar * Sarah J Dunstan Search for this author in: * NPG journals * PubMed * Google Scholar * Bridget Wills Search for this author in: * NPG journals * PubMed * Google Scholar * Jeremy Farrar Search for this author in: * NPG journals * PubMed * Google Scholar * Ta Van Tram Search for this author in: * NPG journals * PubMed * Google Scholar * Tran Thi Gan Search for this author in: * NPG journals * PubMed * Google Scholar * Nguyen Thi Nguyet Binh Search for this author in: * NPG journals * PubMed * Google Scholar * Le Trung Tri Search for this author in: * NPG journals * PubMed * Google Scholar * Le Bich Lien Search for this author in: * NPG journals * PubMed * Google Scholar * Nguyen Minh Tuan Search for this author in: * NPG journals * PubMed * Google Scholar * Nguyen Thi Hong Tham Search for this author in: * NPG journals * PubMed * Google Scholar * Mai Ngoc Lanh Search for this author in: * NPG journals * PubMed * Google Scholar * Nguyen Minh Nguyet Search for this author in: * NPG journals * PubMed * Google Scholar * Nguyen Trong Hieu Search for this author in: * NPG journals * PubMed * Google Scholar * Nguyen Van N Vinh Chau Search for this author in: * NPG journals * PubMed * Google Scholar * Tran Thi Thuy Search for this author in: * NPG journals * PubMed * Google Scholar * Dennis E K Tan Search for this author in: * NPG journals * PubMed * Google Scholar * Anavaj Sakuntabhai Search for this author in: * NPG journals * PubMed * Google Scholar * Yik-Ying Teo Search for this author in: * NPG journals * PubMed * Google Scholar * Martin L Hibberd Contact Martin L Hibberd Search for this author in: * NPG journals * PubMed * Google Scholar * Cameron P Simmons Contact Cameron P Simmons Search for this author in: * NPG journals * PubMed * Google Scholar 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
• Mutations in TRPV4 cause an inherited arthropathy of hands and feet
  - Nat Genet 43(11):1142-1146 (2011)
  Nature Genetics | Letter Mutations in TRPV4 cause an inherited arthropathy of hands and feet * Shireen R Lamandé1, 2 * Yuan Yuan3 * Irma L Gresshoff1, 2 * Lynn Rowley1 * Daniele Belluoccio1 * Kumara Kaluarachchi1 * Christopher B Little4 * Elke Botzenhart5 * Klaus Zerres5 * David J Amor1, 2, 6 * William G Cole7 * Ravi Savarirayan1, 2, 6 * Peter McIntyre3 * John F Bateman1, 8 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:1142–1146Year published:(2011)DOI:doi:10.1038/ng.945Received30 June 2010Accepted24 August 2011Published online02 October 2011 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Familial digital arthropathy-brachydactyly (FDAB) is a dominantly inherited condition that is characterized by aggressive osteoarthropathy of the fingers and toes and consequent shortening of the middle and distal phalanges1. Here we show in three unrelated families that FDAB is caused by mutations encoding p.Gly270Val, p.Arg271Pro and p.Phe273Leu substitutions in the intracellular ankyrin-repeat domain of the cation channel TRPV4. Functional testing of mutant TRPV4 in HEK-293 cells showed that the mutant proteins have poor cell-surface localization. Calcium influx in response to the synthetic TRPV4 agonists GSK1016790A and 4αPDD was significantly reduced, and mutant channels did not respond to hypotonic stress. Others have shown that gain-of-function TRPV4 mutations cause skeletal dysplasias and peripheral neuropathies2, 3, 4, 5, 6, 7, 8, 9, 10, 11. Our data indicate that TRPV4 mutations that reduce channel activity cause a third phenotype, inherited osteoarthropathy, and ! show the importance of TRPV4 activity in articular cartilage homeostasis. Our data raise the possibility that TRPV4 may also have a role in age- or injury-related osteoarthritis. View full text Figures at a glance * Figure 1: Pedigree for family 2, and clinical and radiographical features of individuals with FDAB from families 2 and 3. () Family 2 pedigree. Filled symbols indicate affected individuals; open symbols indicate unaffected individuals; the symbol with a slash through it indicates an individual who was deceased at the time of the study; * indicates individuals included in the linkage study. (,) Photograph () and radiograph () of the hands of individual II:8 from family 2 at 36 years of age showing distal brachydactyly, finger deformities and marked osteoarthropathy of the interphalangeal joints. (,) Photograph () and radiograph () of the left hand of the HDAB-affected individual from family 3 at 36 years of age. * Figure 2: Schematic diagram of the TRPV4 protein. The six transmembrane domains are shown as teal barrels and the six predicted ankyrin repeats as blue barrels. The finger loops linking the ankyrin repeats are numbered. The locations of the N-linked oligosaccharide (N-linked CHO)-modified sites and the Ca2+ pore are indicated. The arthropathy-associated mutations identified in this study (FDAB, orange circles) are clustered in finger loop three. Also shown are the mutations associated with the phenotypic spectrum of skeletal dysplasias (red circles) and peripheral neuropathies (purple circles). Diagram is not drawn to scale. * Figure 3: Expression of wild-type and mutant TRPV4 in stably transfected HEK-293 cells. () Immunodetection of TRPV4 and β-actin (gel-loading control) in whole-cell lysates indicating that TRPV4 is expressed at similar levels in all transfected cell lines. TRPV4 is not detected in untransfected HEK-293 cells. The bands corresponding to the N-glycosylated (TRPV4g) and unglycosylated (TRPV4) forms of TRPV4, which were distinguished by PNGase F digestion, are labeled. Mutant TRPV4 proteins have less complex N-glycosylation (top band) than wild-type TRPV4. () Biotinylated cell-surface proteins were precipitated with streptavidin beads and TRPV4 and transferrin receptors (loading control) detected with specific antibodies. Cell-surface expression of the mutant TRPV4 proteins is poor compared to that of wild-type TRPV4. * Figure 4: Intracellular calcium levels in stably transfected HEK-293 cells. () Constitutive internal fluorescence ratio (mean ± s.e.m.), a reflection of basal [Ca2+]i is shown. All changes relative to untransfected cells or those expressing wild-type TRPV4 were statistically significant (*** indicates P < 0.001). () Changes in intracellular calcium concentration in response to the synthetic TRPV4 agonist GSK1016790A. Cells expressing wild-type TRPV4 showed a dose-dependent increase in [Ca2+]i that reached a plateau at higher concentrations. Cells expressing mutant TRPV4 proteins had reduced responses to GSK1016790A, as demonstrated by smaller dose-dependent increases in [Ca2+]i (mean ± s.e.m., P < 0.01 for all cell lines expressing mutant TRPV4 at 10−6 M GSK1016790A). () Changes in intracellular calcium concentration in response to the synthetic agonist 4αPDD show that cells expressing mutant TRPV4 have a smaller dose-dependent response to the agonist than do cells expressing wild-type TRPV4 (mean ± s.e.m., P < 0.05 at 10−4.5 M 4αPDD for al! l cell lines). () Changes in intracellular calcium concentration in response to hypo-osmolarity (mean ± s.e.m.). Wild-type channels respond with an increase in intracellular calcium levels; mutant channels do not respond to this stimulus. * Figure 5: TRPV4 expression in mouse growth-plate and articular cartilage. Sections of the proximal tibia from a 2-week-old mouse were immunostained for TRPV4 and counterstained with hematoxylin. (,) Immunostaining was performed with antibody to TRPV4 showing protein in articular (arrow) and growth-plate cartilage (arrowhead) () and preimmune serum control (). Images in and are shown at 10× magnification. () TRPV4 protein is localized to the proliferative (P) and prehypertrophic (PH) zones of the growth plate. () Collagen X immunolocalization in the extracellular matrix of the growth-plate hypertrophic zone (H). Images in and are shown at 20× magnification. () Quantitative RT-PCR analysis of Trpv4 mRNA expression in microdissected cartilage zones. Trpv4 expression was normalized to the housekeeping gene Mapk1 and is highest in the proliferative zone. () Immunostaining of an interphalangeal joint of a 2-week-old mouse for TRPV4 shows expression in articular cartilage and the proliferative zone of the growth plate. () Staining with a preimmune seru! m control. * Figure 6: Trpv4 expression in mice with surgically induced osteoarthritis. () Cartilage damage 6 weeks following medial meniscal destabilization (DMM)-induced osteoarthritis in the right knee joint of three mice (1–3) compared to the joints of their sham-operated left knees, visualized by toluidine blue and fast green staining for cartilage and bone, respectively. The damaged cartilage in the knees that underwent DMM is indicated and shows diminished toluidine blue staining (aggrecan loss) and surface fibrillation indicative of osteoarthritis. The bottom row shows stained sections from knees that underwent DMM after laser capture microdissection. () Relative change in Trpv4 mRNA levels in microdissected cartilage from knees that underwent DMM compared to tissue microdissected from the sham-operated cartilage at 1, 2 and 6 weeks after surgery, as measured by quantitative RT-PCR of linearly amplified RNA from pooled microdissected sections. The results represent RNA taken from four mice at weeks 1 and 2 and from three mice at week 6 after surgery. ! (The average of three technical replicates are shown.) The median result at each time point is indicated by a horizontal line. At 6 weeks after surgery, the data are labeled with the mouse identification number (1–3) for comparison to the cartilage histology from the DMM-operated knees shown in . Accession codes * Accession codes * Author information * Supplementary information Referenced accessions Entrez Nucleotide * NM_021625.4 Author information * Accession codes * Author information * Supplementary information Affiliations * Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Australia. * Shireen R Lamandé, * Irma L Gresshoff, * Lynn Rowley, * Daniele Belluoccio, * Kumara Kaluarachchi, * David J Amor, * Ravi Savarirayan & * John F Bateman * Department of Paediatrics, University of Melbourne, Melbourne, Australia. * Shireen R Lamandé, * Irma L Gresshoff, * David J Amor & * Ravi Savarirayan * Department of Pharmacology, University of Melbourne, Melbourne, Australia. * Yuan Yuan & * Peter McIntyre * Raymond Purves Bone & Joint Research Laboratories, Kolling Institute, University of Sydney, Sydney, Australia. * Christopher B Little * Medical Faculty, Institute of Human Genetics, RWTH Aachen University, Aachen, Germany. * Elke Botzenhart & * Klaus Zerres * Genetic Health Services Victoria, Royal Children's Hospital, Melbourne, Australia. * David J Amor & * Ravi Savarirayan * Division of Pediatric Surgery, University of Alberta, Edmonton, Canada. * William G Cole * Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Australia. * John F Bateman Contributions R.S., D.J.A., E.B., K.Z. and W.G.C. recruited the study participants and collected clinical data. S.R.L., J.F.B., P.M., C.B.L. and R.S. designed and supervised the study. I.L.G. performed the linkage analyses, S.R.L. identified the mutations and made the expression constructs and Y.Y. made the transfected cell lines and carried out the calcium imaging and immunoblotting experiments. L.R. and K.K. performed the quantitative RT-PCR and immunostaining. L.R., D.B. and C.B.L. carried out the mouse osteoarthritis experiments. S.R.L. wrote the manuscript. All authors reviewed the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Shireen R Lamandé Author Details * Shireen R Lamandé Contact Shireen R Lamandé Search for this author in: * NPG journals * PubMed * Google Scholar * Yuan Yuan Search for this author in: * NPG journals * PubMed * Google Scholar * Irma L Gresshoff Search for this author in: * NPG journals * PubMed * Google Scholar * Lynn Rowley Search for this author in: * NPG journals * PubMed * Google Scholar * Daniele Belluoccio Search for this author in: * NPG journals * PubMed * Google Scholar * Kumara Kaluarachchi Search for this author in: * NPG journals * PubMed * Google Scholar * Christopher B Little Search for this author in: * NPG journals * PubMed * Google Scholar * Elke Botzenhart Search for this author in: * NPG journals * PubMed * Google Scholar * Klaus Zerres Search for this author in: * NPG journals * PubMed * Google Scholar * David J Amor Search for this author in: * NPG journals * PubMed * Google Scholar * William G Cole Search for this author in: * NPG journals * PubMed * Google Scholar * Ravi Savarirayan Search for this author in: * NPG journals * PubMed * Google Scholar * Peter McIntyre Search for this author in: * NPG journals * PubMed * Google Scholar * John F Bateman Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (713K) Supplementary Note, Supplementary Table 1 and Supplementary Figures 1–5 Additional data
• A primary microcephaly protein complex forms a ring around parental centrioles
  - Nat Genet 43(11):1147-1153 (2011)
  Nature Genetics | Letter A primary microcephaly protein complex forms a ring around parental centrioles * Joo-Hee Sir1, 2 * Alexis R Barr1, 2 * Adeline K Nicholas3 * Ofelia P Carvalho3 * Maryam Khurshid3 * Alex Sossick4 * Stefanie Reichelt1 * Clive D'Santos1 * C Geoffrey Woods3 * Fanni Gergely1, 2 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:1147–1153Year published:(2011)DOI:doi:10.1038/ng.971Received27 June 2011Accepted14 September 2011Published online09 October 2011 Article tools * Full text * 日本語要約 * 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 characterized by a substantial reduction in prenatal human brain growth without alteration of the cerebral architecture and is caused by biallelic mutations in genes coding for a subset of centrosomal proteins1, 2, 3, 4, 5, 6, 7, 8, 9, 10. Although at least three of these proteins have been implicated in centrosome duplication11, the nature of the centrosome dysfunction that underlies the neurodevelopmental defect in MCPH is unclear. Here we report a homozygous MCPH-causing mutation in human CEP63. CEP63 forms a complex with another MCPH protein, CEP152, a conserved centrosome duplication factor12, 13, 14, 15. Together, these two proteins are essential for maintaining normal centrosome numbers in cells. Using super-resolution microscopy, we found that CEP63 and CEP152 co-localize in a discrete ring around the proximal end of the parental centriole, a pattern specifically disrupted in CEP63-deficient cells derived from patien! ts with MCPH. This work suggests that the CEP152-CEP63 ring-like structure ensures normal neurodevelopment and that its impairment particularly affects human cerebral cortex growth. View full text Figures at a glance * Figure 1: Identification of an MCPH-causing mutation in CEP63. () A schematic diagram showing a simplified pedigree. Filled in circles indicate individuals with MCPH. Only the closest link between family members is shown. Photographs of three affected individuals are shown on the right (published here with consent from the family). () The three affected individuals share only one region that was concordantly homozygous in chromosome 3. The region was defined by heterozygous allele results for the markers D3S3513 at 137 cM (121 Mb) and D3S1569 at 158 cM (145 Mb). The three candidate genes sequenced are shown within the linkage interval. () Exons of CEP63 are shown as bars; solid bars represent translated exons. There is a single CpG island for the gene whose transcription starts in exon 3. The nonsense mutation c.129G>A is located in exon 4. A predicted Kozak sequence downstream of the mutation is shown (labeled as 'K'). Alternatively spliced exons are shown in blue and red (Supplementary Fig. 1a). CEP63 is shown with six predicted coile! d-coil domains marked in green. The framed areas correspond to differentially spliced regions. We raised the CEP63 antibody against the recombinant fragment of CEP63 shown. aa, amino acid. () CEP63 protein expression in mouse cerebral cortex neuroepithelium at embryonic day (E) 13.5. The mitotic cell is marked with an asterisk. Twofold magnified views of the framed areas are shown on the right. We co-stained samples with antibodies against CEP63 (red in merge) and the centrosomal protein γ-tubulin (green in merge). DNA is shown in blue. () CEP63 protein expression in lymphocytes from the parent of an affected individual (CEP63+/−) and the affected individual (CEP63−/−). Mitotic cells are marked with asterisks. Threefold magnified views of the centrosomes are shown on the right. We co-stained the cells with antibodies against CEP63 (red in merge) and the centriolar protein centrin 3 (green in merge). DNA is shown in blue. Scale bars, 10 μm. * Figure 2: Disruption of the centrosomal gene CEP63 in vertebrate cells. () We co-stained wild-type (WT) and CEP63KO DT40 cells with antibodies against CEP63 (red in merge) and γ-tubulin (green in merge). Twofold magnified views of framed areas are shown in the insets. DNA is shown in blue. Scale bar, 5 μm. () We probed protein blots of cytoplasmic cell extracts from wild-type and gene-disrupted DT40 cell lines with protein G antibodies. TAP cell lines contain an in-frame GsTAP tag in their CEP63 alleles. α-tubulin served as a loading control. Wb, western blot. () Shown is a summary of the localization and expression of tagged and truncated CEP63 products in the DT40 cell lines specified. n/a, the antibody epitope is largely destroyed in predicted protein product. * Figure 3: CEP63 is required for maintaining normal centrosome numbers. () Examples of mitotic spindle defects in CEP63KO DT40 cells are shown. We stained the cells with antibodies against the centrosome marker CDK5RAP2 (red in merge) and α-tubulin (green in merge). DNA is shown in blue. The graph shows the quantification of spindle phenotypes (n = 3). Scale bar, 5 μm. () The graph shows the number of centrioles in interphase in wild-type and CEP63KO DT40 cells (n = 3). We used antibodies against centrin 3 for this experiment. () The graph shows the number of centrioles in monastrol-induced monopoles of wild-type and CEP63KO DT40 cells (n = 3). Note that centriole numbers 1 and 3 could sometimes reflect insufficient spatial resolution of engaged centriole pairs. Examples for CEP63KO monopoles with different centriole numbers are shown; we co-stained cells with antibodies against the spindle pole marker TACC3 (red in merge) and centrin 3 (green in merge). DNA is shown in blue. Twofold magnified views of centrin 3 staining in the framed areas ar! e shown in the insets. We obtained similar results using polyglutamylated tubulin as the centriole marker; zero to two centrioles were present in 42% of the cells, three or four centrioles were present in 52% of the cells, and more than four centrioles were present in 6% of the cells (a total of 100 CEP63KO mitotic cells). () The graph shows the number of centrioles in untreated monopolar CEP63KO spindles (n = 3). We used antibodies against centrin 3 for the experiment. () The graph shows the number of centrioles in mitotic cells with multipolar spindles (n = 3). On the left, an example of a CEP63KO multipolar spindle is shown with two singlet centrioles (asterisks) at the spindle poles. We co-stained the cell with antibodies against the spindle pole marker TACC3 (red in merge) and centrin 3 (green in merge). DNA is shown in blue. Twofold mangified views of centrin 3 staining in the framed areas are shown in the insets. Scale bars, 5 μm (,). Error bars, mean ± s.d. We obt! ained P values using two-tailed, unpaired Student's t-tests. N! .S., not significant. * Figure 4: CEP63 forms a protein complex with CEP152. () A diagram illustrating the experimental design to identify CEP63-interacting proteins. () A protein blot showing an example of single-step purification of GsTAP-tagged CEP63 protein. We incubated cell lysates of wild-type or TAP-WT DT40 cells (I, input) with streptavidin-agarose resin. We eluted the bound proteins from the resin with biotin (E, eluate). We probed the immunoblot with protein G antibodies to detect GsTAP-tagged CEP63. () We prepared cytoplasmic cell extracts (CCE) from HeLa cells that were mock transfected (−) or transfected with FLAG-CEP63 (+). We used FLAG antibodies for immunoprecipitation (IP). We probed the immunoblots with antibodies against CEP63 and CEP152, as indicated. () We prepared CCEs from HeLa cells that were mock transfected (−) or transfected with FLAG-CEP63-CT (+). We used FLAG antibodies for immunoprecipitation and probed the immunoblots against CEP152 and FLAG, as indicated. * Figure 5: CEP63-dependent centrosomal accumulation of CEP152 maintains normal centrosome numbers. () Localization of Strep-tagged human CEP152 in transfected wild-type and CEP63KO DT40 cells. Threefold magnified views of the framed areas are shown in the panels below. We co-stained the cells with antibodies against centrin 3 (green in merge) and CEP152 (red in merge). () Shown is an outline of the constructs that we transfected into CEP63KO DT40 cells to derive cell lines stably expressing transgenes. () We immunoblotted cytoplasmic cell extracts of CEP63KO-derived DT40 cell lines (nomenclature as in ) with antibodies against CEP152 and, as a loading control, α-tubulin. Below, mitotic cells co-stained with antibodies against centrin 3 (green in merge) and Strep-tag II (red in merge) are shown. Twofold magnified views of the framed areas are shown. DNA is shown in blue. () We immunoblotted cytoplasmic cell extracts of CEP63KO-derived DT40 cell lines (nomenclature as in ) with antibodies against CEP63 and, as a loading control, α-tubulin. Mitotic cells co-stained with an! tibodies against centrin 3 (green in merge) and CEP63 (red in merge) are shown below. Twofold magnified views of the framed areas are shown. DNA is in blue. () The graph depicts the quantification of spindle phenotypes in CEP63KO-derived DT40 cell lines (nomenclature as in ; n = 2; >350 mitotic cells per clone). () The graph depicts the number of centrioles in monastrol-induced monopoles of CEP63KO-CEP152 (c152) or CEP63KO-c152-PACT DT40 cell lines (nomenclature as in ; n = 2). Error bars, mean ± s.d. We obtained P values using two-tailed, unpaired Student's t-tests. Scale bars, 5 μm. * Figure 6: CEP63 and CEP152 form a ring around parental centrioles, a structure disrupted in CEP63−/− cells from affected individuals. () Three-dimensional structured illumination microscope (3D SIM) images are shown of TAP-WT DT40 cells co-stained with antibodies against protein G (which recognizes TAP-CEP63; red in merge) and centrin 3 (green in merge). Each centrosome is shown at twofold magnification, with separate images depicting protein G (top panels) and centrin 3 (middle panels) stainings. The specific cell cycle stages are stated. All images are maximum projections, apart from those referred to as three-dimensional rotations. The latter represent alternative views of the centrioles (generated by rotations of three-dimensional volumes) to highlight particular features. The schematic shows the relative positions of centrin and CEP63 staining. () A 3D SIM image of CEP63+/− human lymphocyte co-stained with antibodies against CEP63 (red in merge) and the daughter centriole marker SAS-6 (green in merge). The schematic shows the relative positions of SAS-6 and CEP63 staining. Scale bar of top image, 3 ! μm. () We co-stained HeLa cells stably expressing FLAG-CEP63 with antibodies against FLAG (green in merge) and CEP152 (red in merge). 3D SIM images of the centrosomes are shown. () 3D SIM images of interphase (top) and mitotic (bottom) CEP63+/− and CEP63−/− human lymphocytes are shown. We co-stained the cells with antibodies against CEP152 (red in merge) and centrin 3 (green in merge). DNA is shown in blue. The framed areas are shown at threefold magnification with the corresponding CEP152 (left panels) and centrin 3 (middle panels) signal. The graphs on the right show percentages of CEP63+/− and CEP63−/− centrosomes with their specific CEP152 localization pattern (n = 2). Error bars, mean ± s.d. () We treated CEP63+/− and CEP63−/− human lymphocytes with dimethyl sulfoxide (DMSO), the PLK1 inhibitor BI 2536 (BI) or monastrol (mon) for 90 min before fixation. We co-stained the cells with antibodies against CEP152 (red in merge) and centrin 3 (green in mer! ge). Examples of centrosomes from individual mitotic cells are! shown. Monastrol and BI 2536 induce monoastral spindle, whereas those in DMSO remain bipolar. Scale bar, 0.5 μm. The distribution of the mean intensities of the centrosomal CEP152 signal in cells from affected individuals is shown in the graph. The number of centrosomes scored were as follows: CEP63+/−, n = 30 DMSO treated and n = 38 BI 2536 treated; and CEP63−/−, n = 26 DMSO treated and n = 24 BI 2536 treated. We measured the background CEP152 signal in areas of CEP63−/− cells that do not contain centrosomes (n = 26). In the box plots, length of whiskers indicates the fifth and ninety-fifth percentiles, the box shows the interquartile (twenty-fifth to seventy-fifth percentile) range and the horizontal line represents the median. We obtained P values using two-tailed, unpaired Student's t-tests. N.S., not significant. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions Ensembl * ENSGALT00000010715 * ENSP00000426129 GenBank * NM_025180.3 * NM_014985.3 Author information * Accession codes * Author information * Supplementary information Affiliations * Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK. * Joo-Hee Sir, * Alexis R Barr, * Stefanie Reichelt, * Clive D'Santos & * Fanni Gergely * Department of Oncology, University of Cambridge, Cambridge, UK. * Joo-Hee Sir, * Alexis R Barr & * Fanni Gergely * Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK. * Adeline K Nicholas, * Ofelia P Carvalho, * Maryam Khurshid & * C Geoffrey Woods * Wellcome Trust/Cancer Research UK Gurdon Institute, Cambridge, UK. * Alex Sossick Contributions J.-H.S. performed most of the experiments presented in the manuscript. A.R.B. generated affected cell lines and performed the initial cell biology analysis. A.K.N. performed molecular genetic mapping and gene mutation identification. O.P.C. performed gene expression analysis in affected cells. M.K. carried out embryonic brain immunohistochemistry. A.S. and S.R. provided support with the super-resolution microscopy. C.D. helped with generation and analysis of proteomic data. C.G.W. performed subject ascertainment, clinical studies and the gene-identification strategy. C.G.W. and F.G. designed the study and wrote the paper, with comments from all authors. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * C Geoffrey Woods or * Fanni Gergely Author Details * Joo-Hee Sir Search for this author in: * NPG journals * PubMed * Google Scholar * Alexis R Barr Search for this author in: * NPG journals * PubMed * Google Scholar * Adeline K Nicholas Search for this author in: * NPG journals * PubMed * Google Scholar * Ofelia P Carvalho Search for this author in: * NPG journals * PubMed * Google Scholar * Maryam Khurshid Search for this author in: * NPG journals * PubMed * Google Scholar * Alex Sossick Search for this author in: * NPG journals * PubMed * Google Scholar * Stefanie Reichelt Search for this author in: * NPG journals * PubMed * Google Scholar * Clive D'Santos Search for this author in: * NPG journals * PubMed * Google Scholar * C Geoffrey Woods Contact C Geoffrey Woods Search for this author in: * NPG journals * PubMed * Google Scholar * Fanni Gergely Contact Fanni Gergely Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (3M) Supplementary Note, Supplementary Figures 1–12, Supplementary Table 2 Excel files * Supplementary Table 1 (37K) Spreadsheet of SILAC results * Supplementary Table 3 (49K) Primer sequences Movies * Supplementary Video 1 (774K) Mitosis in wild-type DT40 cells expressing GFP-α-tubulin. Images were acquired at a rate of 3 minutes/frame. Note that software failed to assign certain frames with correct timestamps. * Supplementary Video 2 (2M) Mitosis in CEP63KO DT40 cells expressing GFP-α-tubulin. Images were acquired at a rate of 3 minutes/frame. * Supplementary Video 3 (610K) Mitosis in wild-type DT40 cells expressing GFP-PACT and Ruby-Histone H2B. Images were acquired at a rate of 6 minutes/frame. GFP is green, ruby is red. * Supplementary Video 4 (1M) Mitosis in wild-type DT40 cells expressing GFP-PACT and Ruby-Histone H2B. Images were acquired at a rate of 6 minutes/frame. Note that one centrosome is weaker. GFP is green, ruby is red. * Supplementary Video 5 (774K) Mitosis in CEP63KO DT40 cells expressing GFP-PACT and Ruby-Histone H2B. Images were acquired at a rate of 6 minutes/frame. GFP is green, ruby is red. * Supplementary Video 6 (2M) Mitosis in CEP63KO DT40 cells expressing GFP-PACT and Ruby-Histone H2B. Images were acquired at a rate of 6 minutes/frame. GFP is green, ruby is red. * Supplementary Video 7 (1M) Mitosis in CEP63KO DT40 cells expressing GFP-PACT and Ruby-Histone H2B. Images were acquired at a rate of 6 minutes/frame. GFP is green, ruby is red. * Supplementary Video 8 (1M) Mitosis in CEP63KO DT40 cells expressing GFP-PACT and Ruby-Histone H2B. Images were acquired at a rate of 6 minutes/frame. GFP is green, ruby is red. Additional data
• Transposon-mediated rewiring of gene regulatory networks contributed to the evolution of pregnancy in mammals
  - Nat Genet 43(11):1154-1159 (2011)
  Nature Genetics | Letter Transposon-mediated rewiring of gene regulatory networks contributed to the evolution of pregnancy in mammals * Vincent J Lynch1 * Robert D Leclerc1 * Gemma May1 * Günter P Wagner1 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:1154–1159Year published:(2011)DOI:doi:10.1038/ng.917Received04 November 2010Accepted01 August 2011Published online25 September 2011 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg A fundamental challenge in biology is explaining the origin of novel phenotypic characters such as new cell types1, 2, 3, 4; the molecular mechanisms that give rise to novelties are unclear5, 6, 7. We explored the gene regulatory landscape of mammalian endometrial cells using comparative RNA-Seq and found that 1,532 genes were recruited into endometrial expression in placental mammals, indicating that the evolution of pregnancy was associated with a large-scale rewiring of the gene regulatory network. About 13% of recruited genes are within 200 kb of a Eutherian-specific transposable element (MER20). These transposons have the epigenetic signatures of enhancers, insulators and repressors, directly bind transcription factors essential for pregnancy and coordinately regulate gene expression in response to progesterone and cAMP. We conclude that the transposable element, MER20, contributed to the origin of a novel gene regulatory network dedicated to pregnancy in placental mamm! als, particularly by recruiting the cAMP signaling pathway into endometrial stromal cells. View full text Figures at a glance * Figure 1: Evolution of the endometrial stromal cell transcriptome in Therian mammals. () Amniote phylogeny showing approximate divergence dates between major lineages; opossum, armadillo and human samples were included in this study. Placental mammals are indicated in red. () Venn diagram showing the intersection of 1:1:1 homologous genes expressed in endometrial cells of human, armadillo and opossum inferred from RNA-Seq. In total, 1,532 genes were scored as expressed in both human and armadillo but not opossum. * Figure 2: MER20s are over-represented near progesterone/cAMP-responsive endometrial genes and have genomic and epigenetic signatures of regulatory elements. () Distribution of distances from differentially regulated stromal genes (N = 6,504) to MER20s in 5-kb bins. Gray bars indicate the total number of MER20s in each bin, and brown bars indicate the distance of the closest MER20 to the gene. The number of genes with MER20s located between transcriptional start and end sites is indicated by 0. The expected number of MER20-associated genes per bin given random positions in the human genome (black line) and compared to genes that were not differentially regulated upon decidualization (blue line) are shown for the location of the closest MER20 to stromally regulated genes (mean ± s.d.). () MER20s are located in regions of the genome with high CpG island density, PhastCons scores and 7× regulatory potential (RP). The profile of histone modifications around MER20s located within 200 kb of genes either up- or downregulated upon differentiation of human ESCs is shown for several methylation and acetylation events and for the vertebra! te insulator protein CTCF. Panel names are colored with respect to the profile shown below. MER20s are centered at position 0 (red box), with normalized ChIP-Seq tag density in 5 bp windows upstream and downstream of the MER20 shown as lines. () Venn diagram showing intersections among MER20s classified by histone modifications as repressors, insulators or enhancers. * Figure 3: MER20s have binding sites for numerous transcription factors, cofactors and insulator proteins and evolve under functional constraints. () The consensus MER20 contains putative binding sites for numerous transcription factors; only sites with a core match of greater than 0.88 are shown. Overlaid plot shows the 3-bp moving average of the per nucleotide substitution rate from a random sample of 500 MER20s. () Nucleotide substitution rates (per 109 years) for various classes of sequence are shown with increasing functional constraint from top to bottom (log scale). Nucleotide substitution rates of putative transcription factor binding sites (pTFBS) and non-binding sites (nonTFBS) from are shown in red. Substitution rates for non-MER20 sequences are shown36. * Figure 4: MER20s are bound by transcription factors and cofactors important for decidualization and pregnancy. () Heat map of ChIP-qPCR data showing fold enrichment of target over normal IgG controls after normalization to input DNA (Enrich.). MER20s are named by their nearest gene. Five MER20s were enriched (>2-fold over background) for FOXO1A, PGR and C/EBPβ, 7 for HoxA-11, 8 for PRMT1/4, 9 for USF1, 10 for p300 and 15 for YY1 and CTCF. () Pairwise Pearson's correlation coefficients (PCCs) calculated for transcription factor binding to MER20s indicates that transcription factors with insulator functions (blue branches) coordinately bind MER20s to the exclusion of transcription factors with enhancer and/or repressor functions (yellow branches) and vice versa. () PCCs indicate that MER20s fall into two distinct groups based on the combination of transcription factors they bind: 'insulator-type' MER20s shown with blue branches and 'enhancer/repressor-type' with yellow branches. * Figure 5: MER20 reporter constructs regulate luciferase expression. () Heat map shows fold changes in luciferase expression between progesterone/cAMP-treated cells and untreated cells transiently transfected with MER20 reporter constructs. Cell types are derived from mammalian cervix (HeLa), lung (A549), kidney (COS-1), muscle (MyoM), keratinocytes (PAM212), chondrocytes (CHON) and endometrial stromal cells (ESC) and chicken fibroblasts (GgaF). () Regulatory strength of MER20s across cell types. Values show the sum of fold changes in luciferase expression upon progesterone/cAMP treatment from Figure 4a. The greatest regulatory strength was observed for ESC, whereas MER20s had only weak regulatory ability in other cell types. () Expression of transcription factors shown to bind MER20s by ChIP across human tissues. The only tissue that coexpresses all transcription factors and cofactors shown to bind MER20s is the uterus. * Figure 6: MER20s are candidate insulator elements. () Insulator-type MER20s are located between differentially expressed genes in human ESC. Cartoon shows the relative locations of genes (named rectangles) and MER20s (small blue or yellow rectangles). The color of each rectangle shows the fold change in expression of that gene upon progesterone/cAMP stimulation in human ESCs (green, downregulation; red, upregulation). White boxes indicate genes not expressed in human ESC. Blue and yellow boxes between genes indicate insulator-type and cis-regulatory–type MER20s, respectively. Black boxes are MER20s that were not characterized in this study. Insulator-type MER20s are significantly more common between differentially expressed genes than expected by chance (P = 0.001, binomial test). Asterisks (*) indicate MER20s that have been previously identified as regulatory elements. () Model of gene regulatory rewiring by MER20s. Ancestrally, numerous genes (black arrows) were not expressed in ESCs because they were repressed by epigen! etic modifications of chromatin and direct silencing by transcriptional repressors. MER20s inserted into the genome in the placental mammal lineage (blue/yellow box on phylogeny), which prevented the spread of silent chromatin, establishing new borders between transcriptionally silent (green) and active (red) chromatin. Author information * Author information * Supplementary information Affiliations * Department of Ecology and Evolutionary Biology & Yale Systems Biology Institute, Yale University, New Haven, Connecticut, USA. * Vincent J Lynch, * Robert D Leclerc, * Gemma May & * Günter P Wagner Contributions V.J.L. and G.P.W. designed experiments and wrote the manuscript. V.J.L. and G.M. performed experiments and analyzed data, and R.D.L. designed and performed bioinformatics analyses. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Vincent J Lynch Author Details * Vincent J Lynch Contact Vincent J Lynch Search for this author in: * NPG journals * PubMed * Google Scholar * Robert D Leclerc Search for this author in: * NPG journals * PubMed * Google Scholar * Gemma May Search for this author in: * NPG journals * PubMed * Google Scholar * Günter P Wagner Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (614K) Supplementary Tables 1 and 2 and Supplementary Figures 1–3 Additional data
• Identification of a functional transposon insertion in the maize domestication gene tb1
  - Nat Genet 43(11):1160-1163 (2011)
  Nature Genetics | Letter Identification of a functional transposon insertion in the maize domestication gene tb1 * Anthony Studer1 * Qiong Zhao1 * Jeffrey Ross-Ibarra2, 3 * John Doebley1 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:1160–1163Year published:(2011)DOI:doi:10.1038/ng.942Received29 April 2011Accepted19 August 2011Published online25 September 2011 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Genetic diversity created by transposable elements is an important source of functional variation upon which selection acts during evolution1, 2, 3, 4, 5, 6. Transposable elements are associated with adaptation to temperate climates in Drosophila7, a SINE element is associated with the domestication of small dog breeds from the gray wolf8 and there is evidence that transposable elements were targets of selection during human evolution9. Although the list of examples of transposable elements associated with host gene function continues to grow, proof that transposable elements are causative and not just correlated with functional variation is limited. Here we show that a transposable element (Hopscotch) inserted in a regulatory region of the maize domestication gene, teosinte branched1 (tb1), acts as an enhancer of gene expression and partially explains the increased apical dominance in maize compared to its progenitor, teosinte. Molecular dating indicates that the Hopscotch ! insertion predates maize domestication by at least 10,000 years, indicating that selection acted on standing variation rather than new mutation. View full text Figures at a glance * Figure 1: Teosinte and maize plants. () Highly branched teosinte plant. () Teosinte lateral branch with terminal tassel. () Unbranched maize plant. () Maize ear shoot (that is, lateral branch). * Figure 2: The phenotypic additive effects for seven intervals across the tb1 genomic region. The horizontal axis represents the tb1 genomic region to scale. Base-pair positions are relative to AGPv2 position 265,745,977 of the maize reference genome sequence. The tb1 ORF and the nearest upstream predicted gene (pg3) are shown. The previously defined control region (CR)14 is shown in red and is divided into its proximal and distal components. Vertical columns represent the additive effects shown with standard error bars for each of the three traits in each of the seven intervals that were tested for an effect on phenotype. Black columns are statistically significant (P (Bonferroni) < 0.05); white bars are not statistically significant (P (Bonferroni) > 0.05). * Figure 3: Sequence diversity in maize and teosinte across the control region. () Nucleotide diversity across the tb1 upstream control region. Base-pair positions are relative to AGPv2 position 265,745,977 of the maize reference genome sequence. P values correspond to HKA neutrality tests for regions A–D, as defined by the dotted lines. Green shading signifies evidence of neutrality, and pink shading signifies regions of non-neutral evolution. Nucleotide diversity (π) for maize (yellow line) and teosinte (green line) were calculated using a 500-bp sliding window with a 25-bp step. The distal and proximal components of the control region with four fixed sequence differences between the most common maize haplotype and teosinte haplotype are shown below. () A minimum spanning tree for the control region with 16 diverse maize and 17 diverse teosinte sequences. Size of the circles for each haplotype group (yellow, maize; green, teosinte) is proportional to the number of individuals within that haplotype. * Figure 4: Constructs and corresponding normalized luciferase expression levels. Transient assays were performed in maize leaf protoplast. Each construct is drawn to scale. The construct backbone consists of the minimal promoter from the cauliflower mosaic virus (mpCaMV, gray box), luciferase ORF (luc, white box) and the nopaline synthase terminator (black box). Portions of the proximal and distal components of the control region (hatched boxes) from maize and teosinte were cloned into restriction sites upstream of the minimal promoter. "Δ" denotes the excision of either the Tourist or Hopscotch element from the maize construct. Horizontal green bars show the normalized mean with s.e.m. for each construct. Author information * Author information * Supplementary information Affiliations * Department of Genetics, University of Wisconsin–Madison, Madison, Wisconsin, USA. * Anthony Studer, * Qiong Zhao & * John Doebley * Department of Plant Sciences, University of California, Davis, California, USA. * Jeffrey Ross-Ibarra * The Genome Center, University of California, Davis, California, USA. * Jeffrey Ross-Ibarra Contributions A.S. and J.D. designed the experiments and wrote the paper. A.S., J.R.-I. and Q.Z. performed population genetic analyses. Genetic mapping, transient assays, sequencing and informatics were done by A.S. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * John Doebley Author Details * Anthony Studer Search for this author in: * NPG journals * PubMed * Google Scholar * Qiong Zhao Search for this author in: * NPG journals * PubMed * Google Scholar * Jeffrey Ross-Ibarra Search for this author in: * NPG journals * PubMed * Google Scholar * John Doebley Contact John Doebley Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (668K) Supplementary Figures 1 and 2 and Supplementary Tables 1–5. 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 43(11):1164 (2011)
  Nature Genetics | Corrigendum Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution * Iris M Heid * Anne U Jackson * Joshua C Randall * Thomas W Winkler * Lu Qi * Valgerdur Steinthorsdottir * Gudmar Thorleifsson * M Carola Zillikens * Elizabeth K Speliotes * Reedik Mägi * Tsegaselassie Workalemahu * Charles C White * Nabila Bouatia-Naji * Tamara B Harris * Sonja I Berndt * Erik Ingelsson * Cristen J Willer * Michael N Weedon * Jian'an Luan * Sailaja Vedantam * Tõnu Esko * Tuomas O Kilpeläinen * Zoltán Kutalik * Shengxu Li * Keri L Monda * Anna L Dixon * Christopher C Holmes * Lee M Kaplan * Liming Liang * Josine L Min * Miriam F Moffatt * Cliona Molony * George Nicholson * Eric E Schadt * Krina T Zondervan * Mary F Feitosa * Teresa Ferreira * Hana Lango Allen * Robert J Weyant * Eleanor Wheeler * Andrew R Wood * Karol Estrada * Michael E Goddard * Guillaume Lettre * Massimo Mangino * Dale R Nyholt * Shaun Purcell * Albert Vernon Smith * Peter M Visscher * Jian Yang * Steven A McCarroll * James Nemesh * Benjamin F Voight * Devin Absher * Najaf Amin * Thor Aspelund * Lachlan Coin * Nicole L Glazer * Caroline Hayward * Nancy L Heard-Costa * Jouke-Jan Hottenga * Åsa Johansson * Toby Johnson * Marika Kaakinen * Karen Kapur * Shamika Ketkar * Joshua W Knowles * Peter Kraft * Aldi T Kraja * Claudia Lamina * Michael F Leitzmann * Barbara McKnight * Andrew P Morris * Ken K Ong * John R B Perry * Marjolein J Peters * Ozren Polasek * Inga Prokopenko * Nigel W Rayner * Samuli Ripatti * Fernando Rivadeneira * Neil R Robertson * Serena Sanna * Ulla Sovio * Ida Surakka * Alexander Teumer * Sophie van Wingerden * Veronique Vitart * Jing Hua Zhao * Christine Cavalcanti-Proença * Peter S Chines * Eva Fisher * Jennifer R Kulzer * Cecile Lecoeur * Narisu Narisu * Camilla Sandholt * Laura J Scott * Kaisa Silander * Klaus Stark * Mari-Liis Tammesoo * Tanya M Teslovich * Nicholas John Timpson * Richard M Watanabe * Ryan Welch * Daniel I Chasman * Matthew N Cooper * John-Olov Jansson * Johannes Kettunen * Robert W Lawrence * Niina Pellikka * Markus Perola * Liesbeth Vandenput * Helene Alavere * Peter Almgren * Larry D Atwood * Amanda J Bennett * Reiner Biffar * Lori L Bonnycastle * Stefan R Bornstein * Thomas A Buchanan * Harry Campbell * Ian N M Day * Mariano Dei * Marcus Dörr * Paul Elliott * Michael R Erdos * Johan G Eriksson * Nelson B Freimer * Mao Fu * Stefan Gaget * Eco J C Geus * Anette P Gjesing * Harald Grallert * Jürgen Gräßler * Christopher J Groves * Candace Guiducci * Anna-Liisa Hartikainen * Neelam Hassanali * Aki S Havulinna * Karl-Heinz Herzig * Andrew A Hicks * Jennie Hui * Wilmar Igl * Pekka Jousilahti * Antti Jula * Eero Kajantie * Leena Kinnunen * Ivana Kolcic * Seppo Koskinen * Peter Kovacs * Heyo K Kroemer * Vjekoslav Krzelj * Johanna Kuusisto * Kirsti Kvaloy * Jaana Laitinen * Olivier Lantieri * G Mark Lathrop * Marja-Liisa Lokki * Robert N Luben * Barbara Ludwig * Wendy L McArdle * Anne McCarthy * Mario A Morken * Mari Nelis * Matt J Neville * Guillaume Paré * Alex N Parker * John F Peden * Irene Pichler * Kirsi H Pietiläinen * Carl G P Platou * Anneli Pouta * Martin Ridderstråle * Nilesh J Samani * Jouko Saramies * Juha Sinisalo * Jan H Smit * Rona J Strawbridge * Heather M Stringham * Amy J Swift * Maris Teder-Laving * Brian Thomson * Gianluca Usala * Joyce B J van Meurs * Gert-Jan van Ommen * Vincent Vatin * Claudia B Volpato * Henri Wallaschofski * G Bragi Walters * Elisabeth Widen * Sarah H Wild * Gonneke Willemsen * Daniel R Witte * Lina Zgaga * Paavo Zitting * John P Beilby * Alan L James * Mika Kähönen * Terho Lehtimäki * Markku S Nieminen * Claes Ohlsson * Lyle J Palmer * Olli Raitakari * Paul M Ridker * Michael Stumvoll * Anke Tönjes * Jorma Viikari * Beverley Balkau * Yoav Ben-Shlomo * Richard N Bergman * Heiner Boeing * George Davey Smith * Shah Ebrahim * Philippe Froguel * Torben Hansen * Christian Hengstenberg * Kristian Hveem * Bo Isomaa * Torben Jørgensen * Fredrik Karpe * Kay-Tee Khaw * Markku Laakso * Debbie A Lawlor * Michel Marre * Thomas Meitinger * Andres Metspalu * Kristian Midthjell * Oluf Pedersen * Veikko Salomaa * Peter E H Schwarz * Tiinamaija Tuomi * Jaakko Tuomilehto * Timo T Valle * Nicholas J Wareham * Alice M Arnold * Jacques S Beckmann * Sven Bergmann * Eric Boerwinkle * Dorret I Boomsma * Mark J Caulfield * Francis S Collins * Gudny Eiriksdottir * Vilmundur Gudnason * Ulf Gyllensten * Anders Hamsten * Andrew T Hattersley * Albert Hofman * Frank B Hu * Thomas Illig * Carlos Iribarren * Marjo-Riitta Jarvelin * W H Linda Kao * Jaakko Kaprio * Lenore J Launer * Patricia B Munroe * Ben Oostra * Brenda W Penninx * Peter P Pramstaller * Bruce M Psaty * Thomas Quertermous * Aila Rissanen * Igor Rudan * Alan R Shuldiner * Nicole Soranzo * Timothy D Spector * Ann-Christine Syvanen * Manuela Uda * André Uitterlinden * Henry Völzke * Peter Vollenweider * James F Wilson * Jacqueline C Witteman * Alan F Wright * Gonçalo R Abecasis * Michael Boehnke * Ingrid B Borecki * Panos Deloukas * Timothy M Frayling * Leif C Groop * Talin Haritunians * David J Hunter * Robert C Kaplan * Kari E North * Jeffrey R O'Connell * Leena Peltonen * David Schlessinger * David P Strachan * Joel N Hirschhorn * Themistocles L Assimes * H-Erich Wichmann * Unnur Thorsteinsdottir * Cornelia M van Duijn * Kari Stefansson * L Adrienne Cupples * Ruth J F Loos * Inês Barroso * Mark I McCarthy * Caroline S Fox * Karen L Mohlke * Cecilia M LindgrenJournal name:Nature GeneticsVolume: 43,Page:1164Year published:(2011)DOI:doi:10.1038/ng1111-1164aPublished online27 October 2011 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Nat. Genet.42, 949–960 (2010); published online 10 October 2010; corrected after print 12 October 2011 In the version of this article initially published, there were errors in Table 1. Specifically, for eight SNPs, the effect allele frequencies were reversed. The correct effect allele frequencies for rs9491696, rs984222, rs4846567, rs1011731, rs718314, rs1294421, rs6795735 and rs2076529 are 0.480, 0.635, 0.717, 0.428, 0.259, 0.613, 0.594 and 0.430, respectively. These errors have been corrected in the HTML and PDF versions of the article. 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• Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis
  - Nat Genet 43(11):1164 (2011)
  Nature Genetics | Corrigendum Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis * George F Mells * James A B Floyd * Katherine I Morley * Heather J Cordell * Christopher S Franklin * So-Youn Shin * Michael A Heneghan * James M Neuberger * Peter T Donaldson * Darren B Day * Samantha J Ducker * Agnes W Muriithi * Elizabeth F Wheater * Christopher J Hammond * Muhammad F Dawwas * David E Jones * Leena Peltonen * Graeme J Alexander * Richard N Sandford * Carl A AndersonJournal name:Nature GeneticsVolume: 43,Page:1164Year published:(2011)DOI:doi:10.1038/ng1111-1164bPublished online27 October 2011 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Nat. Genet.43, 329–332 (2011); published online 13 March 2011; corrected online 12 October 2011 In the version of this article initially published, three authors, Paul Richardson, Ikram Nasr and Richard Aspinall, were inadvertently omitted from the list of the members of the UK PBC Consortium provided in the Supplementary Note. The error has been corrected in the supplementary information file. Additional data Author Details * George F Mells Search for this author in: * NPG journals * PubMed * Google Scholar * James A B Floyd Search for this author in: * NPG journals * PubMed * Google Scholar * Katherine I Morley Search for this author in: * NPG journals * PubMed * Google Scholar * Heather J Cordell Search for this author in: * NPG journals * PubMed * Google Scholar * Christopher S Franklin Search for this author in: * NPG journals * PubMed * Google Scholar * So-Youn Shin Search for this author in: * NPG journals * PubMed * Google Scholar * Michael A Heneghan Search for this author in: * NPG journals * PubMed * Google Scholar * James M Neuberger Search for this author in: * NPG journals * PubMed * Google Scholar * Peter T Donaldson Search for this author in: * NPG journals * PubMed * Google Scholar * Darren B Day Search for this author in: * NPG journals * PubMed * Google Scholar * Samantha J Ducker Search for this author in: * NPG journals * PubMed * Google Scholar * Agnes W Muriithi Search for this author in: * NPG journals * PubMed * Google Scholar * Elizabeth F Wheater Search for this author in: * NPG journals * PubMed * Google Scholar * Christopher J Hammond Search for this author in: * NPG journals * PubMed * Google Scholar * Muhammad F Dawwas Search for this author in: * NPG journals * PubMed * Google Scholar * David E Jones Search for this author in: * NPG journals * PubMed * Google Scholar * Leena Peltonen Search for this author in: * NPG journals * PubMed * Google Scholar * Graeme J Alexander Search for this author in: * NPG journals * PubMed * Google Scholar * Richard N Sandford Search for this author in: * NPG journals * PubMed * Google Scholar * Carl A Anderson Search for this author in: * NPG journals * PubMed * Google Scholar