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• Capture and release
  - Nat Genet 43(10):921 (2011)
  Nature Genetics | Editorial Capture and release Journal name:Nature GeneticsVolume: 43,Page:921Year published:(2011)DOI:doi:10.1038/ng.961Published online28 September 2011 Fostering scientific progress and ensuring that the community has access to human exome data can be difficult to do when faced with the divergent interests of patients, data generators, data funders and potential data users. We support the archiving of sensitive datasets in secure repositories with appropriate mechanisms in place to control access. View full text Additional data
• Whole-genome sequencing data offer insights into human demography
  - Nat Genet 43(10):923-925 (2011)
  Article preview View full access options Nature Genetics | News and Views Whole-genome sequencing data offer insights into human demography * Jonathan K Pritchard1Journal name:Nature GeneticsVolume: 43,Pages:923–925Year published:(2011)DOI:doi:10.1038/ng.953Published online28 September 2011 Two new studies take distinct population genetic approaches to analyzing whole-genome sequencing data sets in order to estimate human demographic parameters. These papers refine our understanding of the relationships among human populations while illustrating both the possibilities and the statistical challenges of fitting demographic models to whole-genome data sets. Article preview Read the full article * Instant access to this article: US$18 Buy now * Subscribe to Nature Genetics for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Author information Article tools * Print * Email * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * Jonathan K. Pritchard is at the Department of Human Genetics, University of Chicago, Chicago, USA. Competing financial interests The author declares no competing financial interests. Corresponding author Correspondence to: * Jonathan K Pritchard Author Details * Jonathan K Pritchard Contact Jonathan K Pritchard Search for this author in: * NPG journals * PubMed * Google Scholar Additional data
• Germline BAP1 mutations and tumor susceptibility
  - Nat Genet 43(10):925-926 (2011)
  Article preview View full access options Nature Genetics | News and Views Germline BAP1 mutations and tumor susceptibility * Alisa M Goldstein1Journal name:Nature GeneticsVolume: 43,Pages:925–926Year published:(2011)DOI:doi:10.1038/ng.956Published online28 September 2011 Two new studies describe germline mutations in BAP1 in putatively dissimilar cancer-related syndromes. The spectrum of neoplasms associated with these germline mutations suggest that BAP1 has an important tumor suppressor function in multiple tissues. Article preview Read the full article * Instant access to this article: US$18 Buy now * Subscribe to Nature Genetics for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Author information Article tools * Print * Email * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * Alisa M. Goldstein is at the Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA. Competing financial interests The author declares no competing financial interests. Corresponding author Correspondence to: * Alisa M Goldstein Author Details * Alisa M Goldstein Contact Alisa M Goldstein Search for this author in: * NPG journals * PubMed * Google Scholar Additional data
• GATA2 mutations lead to MDS and AML
  - Nat Genet 43(10):926-927 (2011)
  Article preview View full access options Nature Genetics | News and Views GATA2 mutations lead to MDS and AML * R. Katherine Hyde1 * P. Paul Liu1 * Affiliations * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:926–927Year published:(2011)DOI:doi:10.1038/ng.949Published online28 September 2011 Several new studies report mutations in the gene GATA2 in three different familial syndromes characterized by predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Before the onset of MDS and AML, patients with similar GATA2 mutations had distinct hematological abnormalities. Article preview Read the full article * Instant access to this article: US$18 Buy now * Subscribe to Nature Genetics for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Author information Article tools * Print * Email * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * R. Katherine Hyde and P. Paul Liu are in the Oncogenesis and Development Section at the National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * P. Paul Liu Author Details * R. Katherine Hyde Search for this author in: * NPG journals * PubMed * Google Scholar * P. Paul Liu Contact P. Paul Liu Search for this author in: * NPG journals * PubMed * Google Scholar Additional data
• Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome)
  - Nat Genet 43(10):929-931 (2011)
  Nature Genetics | Brief Communication Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome) * Pia Ostergaard1, 13 * Michael A Simpson2, 13 * Fiona C Connell3 * Colin G Steward4 * Glen Brice5 * Wesley J Woollard2 * Dimitra Dafou2 * Tatjana Kilo6 * Sarah Smithson7 * Peter Lunt7 * Victoria A Murday8 * Shirley Hodgson5 * Russell Keenan9 * Daniela T Pilz10 * Ines Martinez-Corral11 * Taija Makinen11 * Peter S Mortimer12 * Steve Jeffery1 * Richard C Trembath2 * Sahar Mansour5 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:929–931Year published:(2011)DOI:doi:10.1038/ng.923Received03 May 2011Accepted05 August 2011Published online04 September 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg We report an allelic series of eight mutations in GATA2 underlying Emberger syndrome, an autosomal dominant primary lymphedema associated with a predisposition to acute myeloid leukemia. GATA2 is a transcription factor that plays an essential role in gene regulation during vascular development and hematopoietic differentiation. Our findings indicate that haploinsufficiency of GATA2 underlies primary lymphedema and predisposes to acute myeloid leukemia in this syndrome. View full text Accession codes * Accession codes * Author information * Supplementary information Referenced accessions Entrez Nucleotide * NM_032638 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Pia Ostergaard & * Michael A Simpson Affiliations * Medical Genetics Unit, Biomedical Sciences, St. George's University of London, London, UK. * Pia Ostergaard & * Steve Jeffery * Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, UK. * Michael A Simpson, * Wesley J Woollard, * Dimitra Dafou & * Richard C Trembath * Clinical Genetics, Guy's and St. Thomas' National Health Service (NHS) Foundation Trust, Guy's Hospital, London, UK. * Fiona C Connell * Bone Marrow Transplant Unit, Royal Hospital for Children, Bristol, UK. * Colin G Steward * South West Thames Regional Genetics Service, St. George's University of London, London, UK. * Glen Brice, * Shirley Hodgson & * Sahar Mansour * Haematology Unit, The Children's Hospital at Westmead, Sydney, Australia. * Tatjana Kilo * Department of Clinical Genetics, St Michael's Hospital, Bristol, UK. * Sarah Smithson & * Peter Lunt * Department of Clinical Genetics, Yorkhill Hospital, Glasgow, UK. * Victoria A Murday * Department of Paediatric Haematology, Alderhey Children's Hospital, Liverpool, UK. * Russell Keenan * Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK. * Daniela T Pilz * Lymphatic Development Laboratory, Cancer Research UK London Research Institute, London, UK. * Ines Martinez-Corral & * Taija Makinen * Department of Cardiac and Vascular Sciences, St. George's University of London, London, UK. * Peter S Mortimer Contributions P.S.M., S.J., R.C.T. and S.M. jointly supervised the research. P.O., M.A.S., F.C.C., G.B., P.S.M., S.J., R.C.T. and S.M. conceived and designed the experiments. P.O., M.A.S., W.J.W., D.D., I.M.-C. and T.M. performed the experiments. P.O., M.A.S., D.D. and T.M. performed the statistical analysis. P.O., M.A.S. and T.M. analyzed the data. M.A.S., F.C.C., C.G.S., G.B., T.K., S.S., P.L., V.A.M., S.H., R.K., D.T.P., P.S.M., S.J., R.C.T. and S.M. contributed reagents, materials and analysis tools. M.A.S., S.J., R.C.T. and S.M. wrote the paper. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Sahar Mansour Author Details * Pia Ostergaard Search for this author in: * NPG journals * PubMed * Google Scholar * Michael A Simpson Search for this author in: * NPG journals * PubMed * Google Scholar * Fiona C Connell Search for this author in: * NPG journals * PubMed * Google Scholar * Colin G Steward Search for this author in: * NPG journals * PubMed * Google Scholar * Glen Brice Search for this author in: * NPG journals * PubMed * Google Scholar * Wesley J Woollard Search for this author in: * NPG journals * PubMed * Google Scholar * Dimitra Dafou Search for this author in: * NPG journals * PubMed * Google Scholar * Tatjana Kilo Search for this author in: * NPG journals * PubMed * Google Scholar * Sarah Smithson Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Lunt Search for this author in: * NPG journals * PubMed * Google Scholar * Victoria A Murday Search for this author in: * NPG journals * PubMed * Google Scholar * Shirley Hodgson Search for this author in: * NPG journals * PubMed * Google Scholar * Russell Keenan Search for this author in: * NPG journals * PubMed * Google Scholar * Daniela T Pilz Search for this author in: * NPG journals * PubMed * Google Scholar * Ines Martinez-Corral Search for this author in: * NPG journals * PubMed * Google Scholar * Taija Makinen Search for this author in: * NPG journals * PubMed * Google Scholar * Peter S Mortimer Search for this author in: * NPG journals * PubMed * Google Scholar * Steve Jeffery Search for this author in: * NPG journals * PubMed * Google Scholar * Richard C Trembath Search for this author in: * NPG journals * PubMed * Google Scholar * Sahar Mansour Contact Sahar Mansour Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (352K) Supplementary Methods, Supplementary Tables 1–3 and Supplementary Figures 1–3. Additional data
• Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia
  - Nat Genet 43(10):932-939 (2011)
  Nature Genetics | Article Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia * Priscila P Zenatti1, 13 * Daniel Ribeiro2, 13 * Wenqing Li3, 13 * Linda Zuurbier4 * Milene C Silva2 * Maddalena Paganin5 * Julia Tritapoe3 * Julie A Hixon3 * André B Silveira1 * Bruno A Cardoso2 * Leonor M Sarmento2 * Nádia Correia2 * Maria L Toribio6 * Jörg Kobarg7 * Martin Horstmann8, 9 * Rob Pieters4 * Silvia R Brandalise1, 10 * Adolfo A Ferrando5, 11 * Jules P Meijerink4 * Scott K Durum3 * J Andrés Yunes1, 12, 14 * João T Barata2, 14 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:932–939Year published:(2011)DOI:doi:10.1038/ng.924Received11 April 2011Accepted05 August 2011Published online04 September 2011 Abstract * Abstract * Accession codes * Author information * Supplementary information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Interleukin 7 (IL-7) and its receptor, formed by IL-7Rα (encoded by IL7R) and γc, are essential for normal T-cell development and homeostasis. Here we show that IL7R is an oncogene mutated in T-cell acute lymphoblastic leukemia (T-ALL). We find that 9% of individuals with T-ALL have somatic gain-of-function IL7R exon 6 mutations. In most cases, these IL7R mutations introduce an unpaired cysteine in the extracellular juxtamembrane-transmembrane region and promote de novo formation of intermolecular disulfide bonds between mutant IL-7Rα subunits, thereby driving constitutive signaling via JAK1 and independently of IL-7, γc or JAK3. IL7R mutations induce a gene expression profile partially resembling that provoked by IL-7 and are enriched in the T-ALL subgroup comprising TLX3 rearranged and HOXA deregulated cases. Notably, IL7R mutations promote cell transformation and tumor formation. Overall, our findings indicate that IL7R mutational activation is involved in human T-cel! l leukemogenesis, paving the way for therapeutic targeting of IL-7R–mediated signaling in T-ALL. View full text Figures at a glance * Figure 1: IL7R exon 6 somatic mutations in pediatric T-ALL. () Scheme of IL-7Rα protein (top) and predicted amino acid alterations (bottom). Indicated are the two extracellular fibronectin type III–like domains containing four paired cysteines and a WS×WS motif, the transmembrane domain and the cytoplasmic tail with the Box 1 motif and the tyrosine residues involved in signal transduction. The region where the mutations occur is denoted by an empty box. Amino acid changes involving de novo introduction of a cysteine are indicated in orange; filled boxes denote deletions-insertions and are aligned with the respective deleted amino acid sequence; arrows point to where simple insertions occur. () Representative homoduplex and heteroduplex analysis of PCR products (left) and sequencing chromatograms (right) of paired diagnosis and remission samples indicating the somatic, tumor-associated origin of exon 6 mutations. () Frequency of T-ALL mutations in the three different case cohorts analyzed. * Figure 2: Molecular signatures associated with IL7R mutations in T-ALL. () Heat-map diagram of the 80 top ranking differentially expressed genes (Supplementary Table 1) in IL7R mutant (n = 8) compared to wild-type (n = 109) T-ALLs as determined by empirical Bayes linear models (LIMMA package; cutoff false discovery rate P = 0.05). Genes are shown in rows; each individual sample is shown in one column. The scale bar shows color-coded differential expression from the mean in s.d. units, with red indicating higher expression and blue indicating lower expression. Unsupervised gene expression T-ALL clusters were defined as previously described20 and are indicated as: T (blue), TAL/LMO; T (red), TLX; i (green), immature; and P (violet), proliferative. Cytogenetic defects are denoted as: r, rearranged or mutated; a, aberrant expression; and u, unavailable data. () Gene set enrichment analysis (GSEA) plot (top) showing that genes overexpressed in human normal lymphocytes following IL-7 exposure19 were significantly enriched in IL7R mutant T-ALL cases (e! nrichment score = 0.67, P = 0.045). Heat-map diagram (bottom) of the 12 top-ranking genes in the leading edge. * Figure 3: IL7R mutations induce constitutive signaling in a manner that is independent of IL-7, γc and JAK3 and relies on disulfide bond promotion of homodimer formation. () We analyzed primary T-ALL cells collected at diagnosis from cases with mutant (P1) and wild-type IL7R by immunoblot for JAK1 and STAT5 phosphorylation. (,) We cultured D1 cells expressing human wild-type or mutant (P1 and P2) IL-7Rα without IL-7 for 4 h, stimulated them or not with IL-7 for 20 min and evaluated them for activation of JAK-STAT () and PI3K-Akt () pathway activation by immunoblot. () We analyzed 293T cells reconstituted with JAK3, STAT5 and wild-type or mutant IL-7Rα, and expressing or not expressing γc, for constitutive and IL-7–induced (15 min stimulation) STAT5 phosphorylation. () We transfected 293T cells with IL-7Rα P2 and the remaining components of the IL-7R signaling machinery as indicated and evaluated them for STAT5 phosphorylation. () We transfected 293T cells with IL-7Rα P1 or P2 and small interfering RNA (siRNA) against JAK1 (+) or control non-targeting siRNA (−) and evaluated them after 36 h for JAK1 expression and STAT5 phosphorylatio! n. () Lysates from D1 cells expressing wild-type or mutant IL-7Rα were treated or untreated with the reducing agent DTT and analyzed for IL-7Rα expression by immunoblot. The monomeric and dimeric forms of the receptor are denoted by black and white arrowheads, respectively. () We pretreated 293T cells expressing IL-7Rα P1 and P2 and the remaining components of the IL-7R signaling machinery with β-mercaptoethanol (β-ME), stimulated or unstimulated them with IL-7 for 15 min and subsequently evaluated them for STAT5 phosphorylation by immunoblot. () We analyzed the D1 cells expressing each of the indicated IL-7R constructs for IL-7Rα expression by immunoblot. () We assessed the signaling elicited by each indicated mutant form expressed in D1 (top) or 293T (bottom) cells by detection of STAT5 phosphorylation. * Figure 4: IL7R mutations induce cell-cycle progression, increase cell viability and promote growth factor independence. (,) We cultured Ba/F3 cells stably expressing wild-type or mutant IL-7Rα for 96 h in medium and analyzed them for () cell cycle distribution (percentage of cells in cycle (S+G2/M) is indicated for each condition) and () viability (percentage of viable, early apoptotic and late apoptotic or necrotic cells is indicated in the respective quadrant). () We cultured Ba/F3 cells stably expressing IL-7Rα in the absence of growth factors or with IL-3 or IL-7 and measured expansion at the indicated time points. () We transfected Ba/F3 cells stably expressing P1 or P2 mutant IL-7Rα with siRNA against JAK1, JAK3, γc (IL-2Rγ) or with non-targeting (NT) control and evaluated them for cell viability after 48 h. () We cultured Ba/F3 cells transduced with IL-7Rα P2 or with the indicated introduced mutations in the absence of growth factors and measured expansion at the indicated time points. Results in – represent the average of triplicates ± s.e.m. * Figure 5: In vivo tumorigenic effect of IL7R mutations. We subcutaneously injected D1 cells expressing wild-type or mutant IL-7Rα into Rag1−/− mice and evaluated them for tumor progression and organ infiltration. () Subcutaneous tumor volume growth curves. () Phase contrast and fluorescence imaging of D1 cells (GFP-positive) infiltrated into liver, spleen and bone marrow. () Representative images of spleens from mice culled at day 20 and () respective spleen cellularity. () Histological analysis (hematoxylin and eosin staining) of |indicated organs from a representative mouse transplanted with cells expressing mutant IL-7Rα P2; the right panel shows a 20× magnification of the area denoted by a square on the left panel. () We subcutaneously injected D1 cells expressing wild-type or mutant IL-7Rα into Il7−/−Rag2−/− mice and evaluated them for tumor size at day 20. Results in , and represent the average of triplicates ± s.e.m. * Figure 6: Targeting IL7R mutants using JAK-STAT pathway inhibitors. We cultured Ba/F3 cells expressing mutant IL-7Rα P1 in medium alone in the presence or absence of the indicated doses of different JAK and STAT5 pharmacological inhibitors. () We analyzed the cells at 48 h for effective JAK-STAT pathway inhibition by immunoblot. (,) We analyzed cell viability () at 48 h (INCB018424) and 72 h (CP-690550 and JAK inhibitor 1) after increasing doses of each drug and () at different time points with a single dose of each inhibitor. () We analyzed cell viability at 72 h with increasing doses or at different culture time points with 200 μM of STAT5-specific inhibitor. () We cultured primary T-ALL cells from subject P1 in the presence of the indicated JAK-STAT pathway inhibitors and evaluated them for cell viability at 24 h. Ns, P ≥ 0.05; *P < 0.05; **P < 0.01; ***P < 0.001. Viability results in – represent the average of triplicates ± s.e.m. Accession codes * Abstract * Accession codes * Author information * Supplementary information Referenced accessions Gene Expression Omnibus * GSE26713 Author information * Abstract * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Priscila P Zenatti, * Daniel Ribeiro & * Wenqing Li Affiliations * Laboratório de Biologia Molecular, Centro Infantil Boldrini, Campinas, São Paulo, Brazil. * Priscila P Zenatti, * André B Silveira, * Silvia R Brandalise & * J Andrés Yunes * Cancer Biology Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal. * Daniel Ribeiro, * Milene C Silva, * Bruno A Cardoso, * Leonor M Sarmento, * Nádia Correia & * João T Barata * Immunological Cytokine Group, Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA. * Wenqing Li, * Julia Tritapoe, * Julie A Hixon & * Scott K Durum * Department of Pediatric Oncology/Hematology, Erasmus Medical Center (MC) Sophia Children's Hospital, Rotterdam, The Netherlands. * Linda Zuurbier, * Rob Pieters & * Jules P Meijerink * Institute for Cancer Genetics, Columbia University Medical Center, New York, New York, USA. * Maddalena Paganin & * Adolfo A Ferrando * Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain. * Maria L Toribio * Laboratório Nacional de Biociências (LNBio), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Campinas, São Paulo, Brazil. * Jörg Kobarg * German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL), Hamburg, Germany. * Martin Horstmann * The Research Institute Children's Cancer Center Hamburg, Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. * Martin Horstmann * Serviço de Hematologia/Oncologia Pediátrica, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil. * Silvia R Brandalise * Department of Pathology, Columbia University Medical Center, New York, New York, USA. * Adolfo A Ferrando * Departamento de Genética Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil. * J Andrés Yunes * These authors jointly directed this work. * J Andrés Yunes & * João T Barata Contributions J.T.B. and J.A.Y. conceived and supervised the study. J.T.B., J.A.Y., S.K.D. and J.P.M. designed the experiments. J.T.B. coordinated the different contributions and wrote the paper. J.A.Y., S.K.D., J.P.M., A.A.F., W.L., D.R. and P.P.Z. contributed to the writing of portions of the paper. P.P.Z., D.R., W.L., L.Z., M.C.S., M.P., J.T., J.A.H., A.B.S., B.A.C., L.M.S. and N.C. performed experiments. J.T.B., J.A.Y., S.K.D., J.P.M., A.A.F., P.P.Z., D.R., W.L., M.C.S., A.B.S., N.C. and L.M.S. analyzed the data. M.L.T., J.K., R.P., M.H. and S.R.B. contributed reagents or clinical information. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * João T Barata Author Details * Priscila P Zenatti Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel Ribeiro Search for this author in: * NPG journals * PubMed * Google Scholar * Wenqing Li Search for this author in: * NPG journals * PubMed * Google Scholar * Linda Zuurbier Search for this author in: * NPG journals * PubMed * Google Scholar * Milene C Silva Search for this author in: * NPG journals * PubMed * Google Scholar * Maddalena Paganin Search for this author in: * NPG journals * PubMed * Google Scholar * Julia Tritapoe Search for this author in: * NPG journals * PubMed * Google Scholar * Julie A Hixon Search for this author in: * NPG journals * PubMed * Google Scholar * André B Silveira Search for this author in: * NPG journals * PubMed * Google Scholar * Bruno A Cardoso Search for this author in: * NPG journals * PubMed * Google Scholar * Leonor M Sarmento Search for this author in: * NPG journals * PubMed * Google Scholar * Nádia Correia Search for this author in: * NPG journals * PubMed * Google Scholar * Maria L Toribio Search for this author in: * NPG journals * PubMed * Google Scholar * Jörg Kobarg Search for this author in: * NPG journals * PubMed * Google Scholar * Martin Horstmann Search for this author in: * NPG journals * PubMed * Google Scholar * Rob Pieters Search for this author in: * NPG journals * PubMed * Google Scholar * Silvia R Brandalise Search for this author in: * NPG journals * PubMed * Google Scholar * Adolfo A Ferrando Search for this author in: * NPG journals * PubMed * Google Scholar * Jules P Meijerink Search for this author in: * NPG journals * PubMed * Google Scholar * Scott K Durum Search for this author in: * NPG journals * PubMed * Google Scholar * J Andrés Yunes Search for this author in: * NPG journals * PubMed * Google Scholar * João T Barata Contact João T Barata 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 (852K) Supplementary Figures 1–19 and Supplementary Tables 1 and 2. Additional data
• Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque
  - Nat Genet 43(10):940-947 (2011)
  Nature Genetics | Article Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque * Joshua C Bis1, 80 * Maryam Kavousi2, 3, 80 * Nora Franceschini4, 80 * Aaron Isaacs5, 6, 80 * Gonçalo R Abecasis7, 80 * Ulf Schminke8, 80 * Wendy S Post9, 80 * Albert V Smith10, 80 * L Adrienne Cupples11, 12, 80 * Hugh S Markus13 * Reinhold Schmidt14 * Jennifer E Huffman15 * Terho Lehtimäki16, 17 * Jens Baumert18 * Thomas Münzel19 * Susan R Heckbert20, 21 * Abbas Dehghan2, 3 * Kari North22 * Ben Oostra6, 23 * Steve Bevan13 * Eva-Maria Stoegerer14 * Caroline Hayward15 * Olli Raitakari24, 25 * Christa Meisinger18 * Arne Schillert26 * Serena Sanna27 * Henry Völzke28 * Yu-Ching Cheng29 * Bolli Thorsson10 * Caroline S Fox12, 30 * Kenneth Rice31 * Fernando Rivadeneira3, 32 * Vijay Nambi33, 34, 35 * Eran Halperin36, 37 * Katja E Petrovic38 * Leena Peltonen39, 40 * H Erich Wichmann41 * Renate B Schnabel19 * Marcus Dörr42 * Afshin Parsa43 * Thor Aspelund10, 44 * Serkalem Demissie11 * Sekar Kathiresan45, 46, 47 * Muredach P Reilly48 * the CARDIoGRAM Consortium * Kent Taylor49 * Andre Uitterlinden2, 3, 32 * David J Couper50 * Matthias Sitzer51 * Mika Kähönen17, 52 * Thomas Illig53, 54 * Philipp S Wild19 * Marco Orru27, 55 * Jan Lüdemann56 * Alan R Shuldiner43, 57 * Gudny Eiriksdottir10 * Charles C White11 * Jerome I Rotter49 * Albert Hofman2, 3 * Jochen Seissler58 * Tanja Zeller19 * Gianluca Usala27 * Florian Ernst59 * Lenore J Launer60 * Ralph B D'Agostino Sr61 * Daniel H O'Leary62 * Christie Ballantyne33 * Joachim Thiery63, 64 * Andreas Ziegler26 * Edward G Lakatta65 * Ravi Kumar Chilukoti59 * Tamara B Harris60 * Philip A Wolf12, 66 * Bruce M Psaty1, 21, 67, 68 * Joseph F Polak69 * Xia Li4 * Wolfgang Rathmann70 * Manuela Uda27 * Eric Boerwinkle71 * Norman Klopp53 * Helena Schmidt72 * James F Wilson73 * Jorma Viikari74, 75 * Wolfgang Koenig76 * Stefan Blankenberg19 * Anne B Newman77, 80 * Jacqueline Witteman2, 3, 80 * Gerardo Heiss4, 80 * Cornelia van Duijn3, 5, 6, 80 * Angelo Scuteri65, 80 * Georg Homuth59, 80 * Braxton D Mitchell43, 78, 80 * Vilmundur Gudnason10, 44, 80 * Christopher J O'Donnell12, 79, 80 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:940–947Year published:(2011)DOI:doi:10.1038/ng.920Received02 February 2011Accepted02 August 2011Published online11 September 2011 Abstract * Abstract * Author information * Supplementary information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10−8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Arter! y Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events. View full text Figures at a glance * Figure 1: Genome-wide Manhattan plots for common cIMT and plaque. Plots show the individual P values (based on the discovery meta-analysis) against their genomic position for common cIMT () and the presence of plaque (). Within each chromosome, shown on the x axis, the results are plotted left to right from the p-terminal end. The dotted lines indicate the threshold for follow up, P < 4 × 10−7, and the solid lines indicate the threshold for genome-wide significance, P < 5 × 10−8. The nearest genes are indicated above points that surpassed our significance threshold for follow-up. * Figure 2: Regional plots for common cIMT SNPs. Plots are centered on the most significant SNP at a locus along with the meta-analysis results for SNPs in the 100-kb region surrounding it. All SNPs are plotted with their discovery meta-analysis P values against their genomic position, with the most significant SNP in the region indicated as a red diamond and the other SNPs shaded according to their pairwise correlation (r2) with the signal SNP. The light blue line represents the estimated recombination rates. Gene annotations are shown as dark green lines. * Figure 3: Regional plots for plaque SNPs. Plots are centered on the most significant SNP at each locus along with the meta-analysis results for SNPs in the 100-kb region surrounding it. All SNPs are plotted with their discovery meta-analysis P values against their genomic position, with the most significant SNP in the region indicated as a diamond and the other SNPs shaded according to their pairwise correlation (r2) with the signal SNP. The light blue line represents the estimated recombination rates. Gene annotations are shown as dark green lines. * Figure 4: Forest plots for common cIMT SNP associations. Plots show the study-specific association estimates (β) and 95% confidence intervals for the nine discovery and six second-stage studies (listed in italics) presented as bars. The scale is in ln(cIMT). The association estimate and confidence interval for the meta-analysis combining the discovery and second-stage results are shown as a diamond. Blank spaces indicate occasions in which a particular study was not able to provide results for a given SNP. * Figure 5: Forest plots for plaque SNP associations. Plots show the study-specific association estimates (odds ratios) and 95% confidence intervals for the nine discovery and three second-stage studies (listed in italics) presented as bars. The association estimate and confidence interval for the meta-analysis combining the discovery and second-stage results are shown as a diamond. Blank spaces indicate occasions in which a particular study was not able to provide results for a given SNP. Author information * Abstract * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Joshua C Bis, * Maryam Kavousi, * Nora Franceschini, * Aaron Isaacs, * Gonçalo R Abecasis, * Ulf Schminke, * Wendy S Post, * Albert V Smith, * L Adrienne Cupples, * Anne B Newman, * Jacqueline Witteman, * Gerardo Heiss, * Cornelia van Duijn, * Angelo Scuteri, * Georg Homuth, * Braxton D Mitchell, * Vilmundur Gudnason & * Christopher J O'Donnell Affiliations * Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, Washington, USA. * Joshua C Bis & * Bruce M Psaty * Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. * Maryam Kavousi, * Abbas Dehghan, * Andre Uitterlinden, * Albert Hofman & * Jacqueline Witteman * Netherlands Genomics Initiative (NGI)-Sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, The Netherlands. * Maryam Kavousi, * Abbas Dehghan, * Fernando Rivadeneira, * Andre Uitterlinden, * Albert Hofman, * Jacqueline Witteman & * Cornelia van Duijn * Department of Epidemiology, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA. * Nora Franceschini, * Xia Li & * Gerardo Heiss * Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands. * Aaron Isaacs & * Cornelia van Duijn * Centre for Medical Systems Biology, Leiden, The Netherlands. * Aaron Isaacs, * Ben Oostra & * Cornelia van Duijn * Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA. * Gonçalo R Abecasis * Department of Neurology, Ernst Moritz Arndt University Greifswald, Greifswald, Germany. * Ulf Schminke * Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. * Wendy S Post * Icelandic Heart Association, Kopavogur, Iceland. * Albert V Smith, * Bolli Thorsson, * Thor Aspelund, * Gudny Eiriksdottir & * Vilmundur Gudnason * Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA. * L Adrienne Cupples, * Serkalem Demissie & * Charles C White * National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA. * L Adrienne Cupples, * Caroline S Fox, * Philip A Wolf & * Christopher J O'Donnell * Centre for Clinical Neuroscience, St. George's University of London, London, UK. * Hugh S Markus & * Steve Bevan * Department of Neurology, Medical University Graz, Graz, Austria. * Reinhold Schmidt & * Eva-Maria Stoegerer * Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland. * Jennifer E Huffman & * Caroline Hayward * Department of Clinical Chemistry, University of Tampere, Tampere, Finland. * Terho Lehtimäki * Tampere University Hospital, Tampere, Finland. * Terho Lehtimäki & * Mika Kähönen * Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. * Jens Baumert & * Christa Meisinger * Department of Medicine 2, University Medical Center Mainz, Mainz, Germany. * Thomas Münzel, * Renate B Schnabel, * Philipp S Wild, * Tanja Zeller & * Stefan Blankenberg * Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, Washington, USA. * Susan R Heckbert * Group Health Research Institute, Group Health, Seattle, Washington, USA. * Susan R Heckbert & * Bruce M Psaty * Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina, USA. * Kari North * Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands. * Ben Oostra * Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland. * Olli Raitakari * Department of Clinical Physiology, Turku University Hospital, Turku, Finland. * Olli Raitakari * Institute for Medical Biometry and Statistics, University of Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany. * Arne Schillert & * Andreas Ziegler * Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy. * Serena Sanna, * Marco Orru, * Gianluca Usala & * Manuela Uda * Institute for Community Medicine, Ernst Moritz Arndt University Greifswald, Greifswald, Germany. * Henry Völzke * Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, USA. * Yu-Ching Cheng * Division of Endocrinology, Metabolism, and Diabetes, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. * Caroline S Fox * Department of Biostatistics, University of Washington, Seattle, Washington, USA. * Kenneth Rice * Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. * Fernando Rivadeneira & * Andre Uitterlinden * Baylor College of Medicine, Houston, Texas, USA. * Vijay Nambi & * Christie Ballantyne * Center for Cardiovascular Prevention, The Methodist DeBakey Heart and Vascular Center, Houston, Texas, USA. * Vijay Nambi * Ben Taub General Hospital, Houston, Texas, USA. * Vijay Nambi * The Blavatnik School of Computer Science, Tel-Aviv University, Tel Aviv, Israel. * Eran Halperin * The International Computer Science Institute, Berkeley, California, USA. * Eran Halperin * Department of Neurology, General Hospital and Medical University Graz, Graz, Austria. * Katja E Petrovic * Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. * Leena Peltonen * Institute for Molecular Medicine Finland, Biomedicum, University of Helsinki and National Institute for Health and Welfare, Helsinki, Finland. * Leena Peltonen * Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. * H Erich Wichmann * Department of Internal Medicine B, Ernst Moritz Arndt University Greifswald, Greifswald, Germany. * Marcus Dörr * Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA. * Afshin Parsa, * Alan R Shuldiner & * Braxton D Mitchell * University of Iceland, Reykjavik, Iceland. * Thor Aspelund & * Vilmundur Gudnason * Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA. * Sekar Kathiresan * Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. * Sekar Kathiresan * Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. * Sekar Kathiresan * The Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA. * Muredach P Reilly * Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. * Kent Taylor & * Jerome I Rotter * Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. * David J Couper * Department of Neurology, Klinikum Herford, Herford, Germany. * Matthias Sitzer * Department of Clinical Physiology, University of Tampere, Tampere, Finland. * Mika Kähönen * Research Unit of Molecular Epidemiology, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany. * Thomas Illig & * Norman Klopp * Biobank of the Hannover Medical School, Hannover Medical School, Hannover, Germany. * Thomas Illig * Cardiology Operating Unit, Division of Medicine, Santa Barbara Hospital, Iglesias, Italy. * Marco Orru * Institute of Clinical Chemistry and Laboratory Medicine, Ernst Moritz Arndt University Greifswald, Greifswald, Germany. * Jan Lüdemann * Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland, USA. * Alan R Shuldiner * Ludwig-Maximilians University of Munich, Medical Clinic Innenstadt, Diabetes Center, Munich, Germany. * Jochen Seissler * Interfaculty Institute for Genetics and Functional Genomics, Ernst Moritz Arndt University Greifswald, Greifswald, Germany. * Florian Ernst, * Ravi Kumar Chilukoti & * Georg Homuth * Intramural Research Program, Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. * Lenore J Launer & * Tamara B Harris * Department Mathematics and Statistics, Boston University, Boston, Massachusetts, USA. * Ralph B D'Agostino Sr * St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA. * Daniel H O'Leary * Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany. * Joachim Thiery * Leipzig Research Center of Civilization Diseases, Medical Faculty, University of Leipzig, Leipzig, Germany. * Joachim Thiery * Gerontology Research Center, National Institute on Aging, Baltimore, Maryland, USA. * Edward G Lakatta & * Angelo Scuteri * Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA. * Philip A Wolf * Department of Epidemiology, University of Washington, Seattle, Washington, USA. * Bruce M Psaty * Department of Health Services, University of Washington, Seattle, Washington, USA. * Bruce M Psaty * Department of Radiology, Tufts University School of Medicine, Boston, Massachusetts, USA. * Joseph F Polak * Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany. * Wolfgang Rathmann * University of Texas, School of Public Health, Human Genetics Center, Houston, Texas, USA. * Eric Boerwinkle * Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria. * Helena Schmidt * Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, Scotland. * James F Wilson * Department of Medicine, University of Turku, Turku, Finland. * Jorma Viikari * Turku University Hospital, Turku, Finland. * Jorma Viikari * Department of Internal Medicine II–Cardiology, University of Ulm Medical Center, Ulm, Germany. * Wolfgang Koenig * Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. * Anne B Newman * Department of Epidemiology & Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA. * Braxton D Mitchell * Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston Massachusetts, USA. * Christopher J O'Donnell Consortia * the CARDIoGRAM Consortium Contributions J.C.B., M. Kavousi, N.F., G.R.A., L.A.C., T.L., S.R.H., K.N., C.H., O.R., C.S.F., V.N., R.B.S., T.A., M.S., M. Kähönen, P.S.W., A.R.S., J.I.R., J.S., D.H.O., E.G.L., B.M.P., M.U., E.B., J.V., W.K., S. Blankenberg, A.B.N., J.W., C.v.D., A. Scuteri, V.G., C.J.O. J.C.B., A.I., G.R.A., U.S., W.S.P., H.S.M., R.S., T.L., B.O., S. Bevan, E.-M.S., O.R., C.M., H.V., B.T., F.R., K.E.P., H.E.W., R.B.S., M.D., A.P., T.A., S.K., M.P.R., K.T., A.U., M.S., M. Kähönen, T.I., P.S.W., M.O., J.L., A.R.S., G.E., J.I.R., A.H., J.S., T.Z., G.U., F.E., L.J.L., R.B.D., D.H.O., J.T., T.B.H., P.A.W., B.M.P., J.F.P., W.R., E.B., N.K., H.S., J.F.W., J.V., W.K., S. Blankenberg, A.B.N., G. Heiss, C.v.D., A. Scuteri, G. Homuth, B.D.M., V.G., C.J.O. J.C.B., M. Kavousi, N.F., A.I., G.R.A., A.V.S., L.A.C., J.E.H., T.L., J.B., S.R.H., A.D., K.N., C.H., O.R., A. Schillert, S.S., Y.-C.C., K.R., V.N., E.H., K.E.P., T.A., S.D., S.K., P.S.W., C.C.W., R.B.D., A.Z., R.K.C., H.S., C.J.O. J.C.B., M. Kavousi, N.F., A.I., K.N., O.R., M. Kähönen, J.F.P., J.V., C.J.O. J.C.B., M. Kavousi, N.F., A.I., G.R.A., U.S., W.S.P., L.A.C., H.S.M., R.S., T.L., J.B., T.M., S.R.H., A.D., K.N., O.R., C.M., H.V., B.T., K.R., F.R., V.N., H.E.W., R.B.S., M.D., A.P., S.D., M.P.R., K.T., A.U., D.J.C., M.S., M. Kähönen, T.I., J.L., G.E., J.I.R., A.H., J.S., F.E., L.J.L., R.B.D., D.H.O., C.B., A.Z., E.G.L., R.K.C., T.B.H., B.M.P., J.F.P., X.L., W.R., E.B., J.V., W.K., S. Blankenberg, J.W., C.v.D., A. Scuteri, G. Homuth, B.D.M., V.G., C.J.O. G.R.A., U.S., H.S.M., R.S., T.L., O.R., H.V., L.P., M.D., S.K., A.U., M.S., M. Kähönen, P.S.W., A.R.S., J.I.R., A.H., J.S., A.Z., P.A.W., B.M.P., J.F.P., W.R., M.U., E.B., H.S., J.F.W., J.V., W.K., A.B.N., G. Heiss, C.v.D., G. Homuth, B.D.M., V.G., C.J.O. Competing financial interests V.N. has a non-financial research collaboration with General Electric and Medipattern Inc. Corresponding authors Correspondence to: * Joshua C Bis or * Christopher J O'Donnell Author Details * Joshua C Bis Contact Joshua C Bis Search for this author in: * NPG journals * PubMed * Google Scholar * Maryam Kavousi Search for this author in: * NPG journals * PubMed * Google Scholar * Nora Franceschini Search for this author in: * NPG journals * PubMed * Google Scholar * Aaron Isaacs Search for this author in: * NPG journals * PubMed * Google Scholar * Gonçalo R Abecasis Search for this author in: * NPG journals * PubMed * Google Scholar * Ulf Schminke Search for this author in: * NPG journals * PubMed * Google Scholar * Wendy S Post Search for this author in: * NPG journals * PubMed * Google Scholar * Albert V Smith Search for this author in: * NPG journals * PubMed * Google Scholar * L Adrienne Cupples Search for this author in: * NPG journals * PubMed * Google Scholar * Hugh S Markus Search for this author in: * NPG journals * PubMed * Google Scholar * Reinhold Schmidt Search 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PubMed * Google Scholar * Christopher J O'Donnell Contact Christopher J O'Donnell Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary Text and Figures (2M) Supplementary Figures 1–6, Supplementary Tables 1–7 and Supplementary Note. Additional data
• Pol III binding in six mammals shows conservation among amino acid isotypes despite divergence among tRNA genes
  - Nat Genet 43(10):948-955 (2011)
  Nature Genetics | Article Pol III binding in six mammals shows conservation among amino acid isotypes despite divergence among tRNA genes * Claudia Kutter1, 2, 7 * Gordon D Brown1, 7 * Ângela Gonçalves3, 4 * Michael D Wilson1, 2 * Stephen Watt1 * Alvis Brazma3 * Robert J White5 * Duncan T Odom1, 2, 6 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:948–955Year published:(2011)DOI:doi:10.1038/ng.906Received18 January 2011Accepted15 July 2011Published online28 August 2011 Abstract * Abstract * Accession codes * Author information * Supplementary information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg RNA polymerase III (Pol III) transcription of tRNA genes is essential for generating the tRNA adaptor molecules that link genetic sequence and protein translation. By mapping Pol III occupancy genome-wide in mouse, rat, human, macaque, dog and opossum livers, we found that Pol III binding to individual tRNA genes varies substantially in strength and location. However, when we took into account tRNA redundancies by grouping Pol III occupancy into 46 anticodon isoacceptor families or 21 amino acid–based isotype classes, we discovered strong conservation. Similarly, Pol III occupancy of amino acid isotypes is almost invariant among transcriptionally and evolutionarily diverse tissues in mouse. Thus, synthesis of functional tRNA isotypes has been highly constrained, although the usage of individual tRNA genes has evolved rapidly. View full text Figures at a glance * Figure 1: Pol III occupies and transcribes tRNA genes in mouse liver. () tRNA genes are present in hundreds of copies in a mammalian genome but collapse into 62 isoacceptor families (48 in mammals) and 21 amino acid isotypes. () Separate portions of each species' tissues were flash-frozen to permit direct RNA sequencing and treated with formaldehyde to cross-link protein-DNA contacts to allow ChIP reactions. () Primary tissues were isolated from six mammals varying in evolutionary distance from mouse, from 12 million years (rat) to >180 million years (opossum). () Typical Pol III–bound tRNA loci on mouse chromosome 11. Pol III binding, beige enrichment track (top); input DNA, black track (middle); total RNA, blue track (bottom), indicating Pol III–bound regions are transcriptionally active. The y axis of each track specifies read density. The mammalian conservation track, obtained from UCSC, shows degree of placental mammal base pair conservation (20 species) and sequence constraint. Bottom, genome annotation in this region obtained for re! peats, noncoding RNAs and tRNAs (UCSC genome browser). * Figure 2: tRNA isoacceptors and isotypes are differentially bound by Pol III in mouse liver. () Pol III binding varies widely among isoacceptor families (red), which collapse in number and binding variability in the 21 amino acid isotypes (gray). Areas are shaded according to number of Pol III read counts (dendrogram, white, low; red/black, high). Hatched boxes, isoacceptors absent in mouse or that do not encode an amino acid. (–) Pol III binding between replicates of mouse liver compared at tRNA gene loci (blue, ), anticodon isoacceptors (red, ) and amino acid isotypes (black, ). Spearman's rank correlation coefficients (ρ) are shown. * Figure 3: Amino acid isotypes are bound by Pol III in a tissue-independent manner. Pol III occupancy at tRNA genes was determined in mouse liver, muscle and testes. Intersection of row-column for each tissue combination in top right triangle, correlation for all Pol III–bound tRNA gene loci (blue) and isoacceptor (red); bottom-left triangle, binding of Pol III to isotypes (black). Spearman's rank correlation coefficients (ρ) are reported correspondingly by color in bottom right of each intertissue panel. * Figure 4: The tRNA genes bound by Pol III diverge in genomic location and functional usage among mammals. () Two clusters of multiple tRNA genes, flanking the homologs of the mouse genes Trim41 and Trim7, are bound by Pol III in multiple species (shown as genome tracks). Mmu, mouse; Rno, rat; Hsa, human; Mml, macaque; Cfa, dog; Mdo, short-tailed opossum. Numbers on left of each track specify read density for Pol III ChIP experiments. The syntenic position of each tRNA gene is traced between species with a dashed line. Blue dashed line, conserved binding in all six mammals; yellow dashed line, species-specific innovation. Cluster upstream of the Trim41 gene shows four tRNA gene loci (two valines, a lysine and an alanine) with conserved Pol III binding. The lysine gene locus does not exist in the rodents, and two leucines are only present in opossum. An additional cluster 3′ downstream of Trim7 demonstrates two tRNA loci (threonine and proline) bound by Pol III in all six species. The valine tRNA gene evolved only in the eutherians, and the leucine tRNA gene is not bound in dog.! () A five-way Venn diagram intersects the tRNA genes bound by Pol III for each possible combination of eutherian mammals used in this study. Total number of species-specific tRNA genes (white) is subdivided into tRNA genes present (inner black numbers) and absent (outer black numbers in dashed subdivision) in Ensembl's 16 amniote alignment. Area colorings are shaded according to number of tRNA genes (white, low; blue, high). () tRNA loci bound by Pol III from were sorted by number of species in which they were bound, and compared to Pol III occupancy in each of the study species (Online Methods). * Figure 5: Pol III occupancy and codon usage across mammalian evolution. We experimentally determined the strength of Pol III binding using ChIP-seq () and transcript abundance using mRNA-seq () in livers of six mammals. () Proportional frequency of Pol III binding by isotype among all six mammals. () Proportional frequency of Pol III binding to all possible arginine tRNA isoacceptors. () Pol III binding to tRNA anticodons (filled circles) and to isotypes (hollow circles) across 180 million years of mammalian evolution. () The frequency of each amino acid weighted by transcript expression between species. () Proportional frequencies of codon usage for arginine. () Triplet codon (filled circles) and amino acid usage (hollow circles) across 180 million years of mammalian evolution. Colored lines within the radial plots (,, and ) present data values of each species (purple, mouse; pink, rat; green, human; orange, macaque; black, dog; and yellow, opossum). Labels around plot indicate amino acids ( and ), anticodons () and triplet codons (). Labels wi! thin grid of radial plots (,, and ) describe percentages. Accession codes * Abstract * Accession codes * Author information * Supplementary information Referenced accessions ArrayExpress * E-MTAB-424 * E-MTAB-442 Sequence Read Archive * SRA001030 Author information * Abstract * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Claudia Kutter & * Gordon D Brown Affiliations * Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK. * Claudia Kutter, * Gordon D Brown, * Michael D Wilson, * Stephen Watt & * Duncan T Odom * University of Cambridge, Department of Oncology, Hutchison/Medical Research Council Research Centre, Cambridge, UK. * Claudia Kutter, * Michael D Wilson & * Duncan T Odom * European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK. * Ângela Gonçalves & * Alvis Brazma * University of Cambridge, Graduate School of Life Sciences, Cambridge, UK. * Ângela Gonçalves * Beatson Institute for Cancer Research, Glasgow, UK. * Robert J White * Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. * Duncan T Odom Contributions C.K., G.D.B. and D.T.O. conceived experiments. C.K., S.W. and M.D.W. carried out experiments. G.D.B., C.K. and A.G. analyzed the data. C.K., G.D.B., A.B., R.J.W. and D.T.O. wrote the paper. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Duncan T Odom Author Details * Claudia Kutter Search for this author in: * NPG journals * PubMed * Google Scholar * Gordon D Brown Search for this author in: * NPG journals * PubMed * Google Scholar * Ângela Gonçalves Search for this author in: * NPG journals * PubMed * Google Scholar * Michael D Wilson Search for this author in: * NPG journals * PubMed * Google Scholar * Stephen Watt Search for this author in: * NPG journals * PubMed * Google Scholar * Alvis Brazma Search for this author in: * NPG journals * PubMed * Google Scholar * Robert J White Search for this author in: * NPG journals * PubMed * Google Scholar * Duncan T Odom Contact Duncan T Odom Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Accession codes * Author information * Supplementary information Excel files * Supplementary Table 2 (241K) Genomic location of pol III-bound mouse tRNA genes * Supplementary Table 3 (100K) Genomic location of pol III-bound rat tRNA genes * Supplementary Table 4 (89K) Genomic location of pol III-bound human tRNA genes * Supplementary Table 5 (86K) Genomic location of pol III-bound macaque tRNA genes * Supplementary Table 6 (66K) Genomic location of pol III-bound dog tRNA genes * Supplementary Table 7 (81K) Genomic location of pol III-bound opossum tRNA genes PDF files * Supplementary Text and Figures (3M) Supplementary Figures 1–14 and Supplementary Tables 1 and 8–11 Additional data
• Whole-genome sequencing of multiple Arabidopsis thaliana populations
  - Nat Genet 43(10):956-963 (2011)
  Nature Genetics | Article Whole-genome sequencing of multiple Arabidopsis thaliana populations * Jun Cao1, 8 * Korbinian Schneeberger1, 2, 8 * Stephan Ossowski1, 3, 4, 8 * Torsten Günther5, 8 * Sebastian Bender1 * Joffrey Fitz1 * Daniel Koenig1 * Christa Lanz1 * Oliver Stegle6 * Christoph Lippert6 * Xi Wang1 * Felix Ott1 * Jonas Müller1 * Carlos Alonso-Blanco7 * Karsten Borgwardt6 * Karl J Schmid5 * Detlef Weigel1 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:956–963Year published:(2011)DOI:doi:10.1038/ng.911Received08 March 2011Accepted26 July 2011Published online28 August 2011 Abstract * Abstract * Author information * Supplementary information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg The plant Arabidopsis thaliana occurs naturally in many different habitats throughout Eurasia. As a foundation for identifying genetic variation contributing to adaptation to diverse environments, a 1001 Genomes Project to sequence geographically diverse A. thaliana strains has been initiated. Here we present the first phase of this project, based on population-scale sequencing of 80 strains drawn from eight regions throughout the species' native range. We describe the majority of common small-scale polymorphisms as well as many larger insertions and deletions in the A. thaliana pan-genome, their effects on gene function, and the patterns of local and global linkage among these variants. The action of processes other than spontaneous mutation is identified by comparing the spectrum of mutations that have accumulated since A. thaliana diverged from its closest relative 10 million years ago with the spectrum observed in the laboratory. Recent species-wide selective sweeps are ! rare, and potentially deleterious mutations are more common in marginal populations. View full text Figures at a glance * Figure 1: Sequencing of 80 A. thaliana strains. () Location of the eight geographic regions sampled. The smaller ones, such as Swabia in the southwest of Germany, are not indicated to scale. Pie charts indicate STRUCTURE results for k = 5 (for other values of k, see Supplementary Fig. 4). () Distribution of polymorphisms across sequence classes. SVs covering several sequence classes were attributed to only one class, in the order coding sequence > untranslated region (UTR) > intron > transposable element (TE) > intergenic sequence. The sequence space of 112.3 Mb (94.3% of the reference genome) comprised all sites for which the quality threshold was exceeded in at least one accession. () SNP coverage by accession. Blue, all SNPs; purple, private SNPs excluded; orange, private and region-specific SNPs excluded. Solid lines, optimized order of strains; dashed lines, arrangement of strains in reverse order. () Allele frequency of transposable elements present in reference but missing in at least one of the 80 strains. () Accu! racy and percentage of missing genotypes for SNP imputation over a range of imputation thresholds, considering the 80 genomes as a reference panel (3,184 SNPs with <10% missing data) and 216,000 tag SNPs in test accessions. * Figure 2: Detection of sequences not present in the reference. () Length distribution of de novo–assembled contigs. Note that this is almost certainly an underestimate, because several accessions yielded few such contigs (Supplementary Table 1). () Allele frequency of CNVs. () Clustering of accessions for each CNV based on coverage relative to the reference; different clusters had to have at least twofold differences in average coverage. () Example of a CNV region in two Central Asian accessions. Open diamonds denote pseudo-heterozygous SNPs indicating the presence of different sequences in the inbred genomes; open squares indicate positions of reads for which the corresponding read mate mapped to the reference genome. Although the pattern in ICE150 is consistent with a simple duplication, the situation in Sha appears to be more complex. () Relative coverage of CNV shown in in 80 accessions, indicating different copy numbers in two groups of Central Asian accessions. * Figure 3: Patterns of allele sharing among populations. () SNPs that are region specific (triangles) or shared between regions (horizontal bars). Box plots indicate distribution of accession-specific SNPs. () Decay of LD, expressed as r2, in seven individuals from each region or from all individuals. * Figure 4: Footprints of selection. () Haplotype diversity (continuous lines; window size 10 kb, scale on the left) and LD in Caucasus accessions (vertical bars; window size 5 kb, scale on the right) on chromosomes 1 and 2. 'A' marks the sweep candidate on chromosome 1, and 'B' marks the high-LD block on chromosome 2. () Minor-allele frequency, window size 200 kb. () Genome-wide wiHS statistics30, window size 10 kb. () FST, calculated for all SNPs, with window size of 50 SNPs and a local polynomial regression performed. 'C' marks the highest non-centromere peak. See Supplementary Figure 6 for other chromosomes and regions. * Figure 5: Mutational spectrum. () Rates of the six different types of polymorphisms, polarized against A. lyrata. Rates of G:CA:T type polymorphisms were set to a reference level of 1 such that for DAF ≤ 0.1, 1 equals 0.016 per site, and for DAF ≥ 0.9, 1 equals 0.002 per site. For comparison, inset shows spontaneous mutation spectrum in A. thaliana15, where 1 equals 1 × 10−8 per site per generation. () Distribution of intergenic transitions in 200-kb windows along chromosomes. See Supplementary Figure 7 for other site types. (,) Polymorphism density as a function of position on chromosome and alignability to A. lyrata. * Figure 6: Deleterious polymorphisms. () Incidence of drastic mutations in major gene families. () Minor- and derived-allele frequencies of polymorphisms with different functional annotation. () Relationship between frequency spectrum of apparent deleterious mutations and population size. Shown is the correlation between estimated effective population size and the slope of the regression lines of the ratio between deleterious and tolerated mutations versus their derived allele frequencies for each geographic region. More negative values indicate stronger selection against inferred deleterious mutations41 (Supplementary Fig. 10). Author information * Abstract * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Jun Cao, * Korbinian Schneeberger, * Stephan Ossowski & * Torsten Günther Affiliations * Max Planck Institute for Developmental Biology, Tübingen, Germany. * Jun Cao, * Korbinian Schneeberger, * Stephan Ossowski, * Sebastian Bender, * Joffrey Fitz, * Daniel Koenig, * Christa Lanz, * Xi Wang, * Felix Ott, * Jonas Müller & * Detlef Weigel * Max Planck Institute of Plant Breeding Research, Cologne, Germany. * Korbinian Schneeberger * Center for Genomic Regulation, Barcelona, Spain. * Stephan Ossowski * Universitat Pompeu Fabra, Barcelona, Spain. * Stephan Ossowski * Institute of Plant Breeding, Seed Science and Population Genetics, University of Hohenheim, Stuttgart, Germany. * Torsten Günther & * Karl J Schmid * Machine Learning and Computational Biology Research Group, Max Planck Institute for Intelligent Systems and Max Planck Institute for Developmental Biology, Tübingen, Germany. * Oliver Stegle, * Christoph Lippert & * Karsten Borgwardt * Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain. * Carlos Alonso-Blanco Contributions J.C., K.S., S.O., K.J.S. and D.W. designed the study. C.A.-B. and K.J.S. provided biological material. J.C., D.K. and C. Lanz generated the sequencing data. J.C., K.S., S.O., X.W. and F.O. performed primary analysis of the sequencing data. J.C., K.S., S.O. and S.B. identified and annotated polymorphisms. J.C., J.M. and T.G. performed population genomic analyses. O.S., C. Lippert and K.B. performed imputations. J.F. developed web tools. J.C., K.J.S. and D.W. wrote the manuscript with contributions from all authors. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Detlef Weigel Author Details * Jun Cao Search for this author in: * NPG journals * PubMed * Google Scholar * Korbinian Schneeberger Search for this author in: * NPG journals * PubMed * Google Scholar * Stephan Ossowski Search for this author in: * NPG journals * PubMed * Google Scholar * Torsten Günther Search for this author in: * NPG journals * PubMed * Google Scholar * Sebastian Bender Search for this author in: * NPG journals * PubMed * Google Scholar * Joffrey Fitz Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel Koenig Search for this author in: * NPG journals * PubMed * Google Scholar * Christa Lanz Search for this author in: * NPG journals * PubMed * Google Scholar * Oliver Stegle Search for this author in: * NPG journals * PubMed * Google Scholar * Christoph Lippert Search for this author in: * NPG journals * PubMed * Google Scholar * Xi Wang Search for this author in: * NPG journals * PubMed * Google Scholar * Felix Ott Search for this author in: * NPG journals * PubMed * Google Scholar * Jonas Müller Search for this author in: * NPG journals * PubMed * Google Scholar * Carlos Alonso-Blanco Search for this author in: * NPG journals * PubMed * Google Scholar * Karsten Borgwardt Search for this author in: * NPG journals * PubMed * Google Scholar * Karl J Schmid Search for this author in: * NPG journals * PubMed * Google Scholar * Detlef Weigel Contact Detlef Weigel Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Author information * Supplementary information Excel files * Supplementary Table 3 (991K) CNVs, SNPs with predicted drastic effects on gene function, and SV deletions that overlap coding sequences by at least 50 bp. PDF files * Supplementary Text and Figures (15M) Supplementary Note, Supplementary Tables 1, 2, 4 and 5 and Supplementary Figures 1–10 Additional data
• Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion
  - Nat Genet 43(10):964-968 (2011)
  Nature Genetics | Letter Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion * Adam J Bass1, 2, 3, 4, 20 * Michael S Lawrence4, 20 * Lear E Brace1 * Alex H Ramos1, 4 * Yotam Drier5 * Kristian Cibulskis4 * Carrie Sougnez4 * Douglas Voet4 * Gordon Saksena4 * Andrey Sivachenko4 * Rui Jing4 * Melissa Parkin4 * Trevor Pugh1, 4 * Roel G Verhaak1, 4 * Nicolas Stransky4 * Adam T Boutin1 * Jordi Barretina4 * David B Solit6 * Evi Vakiani7 * Wenlin Shao8 * Yuji Mishina8 * Markus Warmuth8 * Jose Jimenez9 * Derek Y Chiang10 * Sabina Signoretti11, 12 * William G Kaelin1, 2 * Nicole Spardy1 * William C Hahn1, 2, 3, 4 * Yujin Hoshida4 * Shuji Ogino1, 11, 12, 13 * Ronald A DePinho1, 2, 14, 15 * Lynda Chin1, 4, 15, 16 * Levi A Garraway1, 2, 3, 4 * Charles S Fuchs1, 2, 13 * Jose Baselga9, 17 * Josep Tabernero9 * Stacey Gabriel4 * Eric S Lander4, 18, 19 * Gad Getz4 * Matthew Meyerson1, 3, 4, 11 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:964–968Year published:(2011)DOI:doi:10.1038/ng.936Received29 March 2011Accepted11 August 2011Published online04 September 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Prior studies have identified recurrent oncogenic mutations in colorectal adenocarcinoma1 and have surveyed exons of protein-coding genes for mutations in 11 affected individuals2, 3. Here we report whole-genome sequencing from nine individuals with colorectal cancer, including primary colorectal tumors and matched adjacent non-tumor tissues, at an average of 30.7× and 31.9× coverage, respectively. We identify an average of 75 somatic rearrangements per tumor, including complex networks of translocations between pairs of chromosomes. Eleven rearrangements encode predicted in-frame fusion proteins, including a fusion of VTI1A and TCF7L2 found in 3 out of 97 colorectal cancers. Although TCF7L2 encodes TCF4, which cooperates with β-catenin4 in colorectal carcinogenesis5, 6, the fusion lacks the TCF4 β-catenin–binding domain. We found a colorectal carcinoma cell line harboring the fusion gene to be dependent on VTI1A-TCF7L2 for anchorage-independent growth using RNA interf! erence-mediated knockdown. This study shows previously unidentified levels of genomic rearrangements in colorectal carcinoma that can lead to essential gene fusions and other oncogenic events. View full text Figures at a glance * Figure 1: DNA structural rearrangements and copy number alterations detected in the nine colorectal tumors displayed as CIRCOS plots33. Chromosomes are arranged circularly end-to-end with each chromosome's cytobands marked in the outer ring. The inner ring displays copy number data inferred from whole-genome sequencing with blue indicating losses and red indicating gains. Within the circle, rearrangements are shown as arcs with intrachromosomal events in green and interchromosomal translocations in purple. * Figure 2: Complex rearrangements between chromosome pairs in two colorectal carcinomas. The central portion of the figure contains copy-number profiles across all chromosomes with the chromosome identity labeled across the x axis and the scale for copy-number ratio (log2) depicted on the y axis of each plot. The upper plot shows the tumor CRC-4, and the lower plot shows the copy-number profile for CRC-6, with the black dots marking the copy-number ratio inferred along each locus across the genome. The upper inset boxes show detailed views of the copy numbers and rearrangements for chromosomes 8 (dark blue) and 20 (ochre) for CRC-4 with the centromere labeled as a purple circle. Rearrangements detected by dRanger are shown in green (intrachromosomal) and purple (interchromosomal). The lower inset boxes show detailed copy-number and rearrangement images for CRC-6, with inset boxes showing chromosome 5 (red) and 11 (gray), with lines marking positions of genomic rearrangements. * Figure 3: Recurrent gene fusion between VTI1A and TCF7L2. () The upper schematic depicts the positions of exons (vertical lines) within VTI1A and TCF7L2, which reside adjacent to each other on chromosome 10. The blowup displays the locations of discordant paired-end reads found in tumor CRC-9 for which one read (labeled in blue) is in an intron of VTI1A and the other read (labeled in red) is in an intron of TCF7L2. () The upper schematic depicts the structure of the predicted fusion transcript generated by the fusion. The presence of the exact reads spanning the fusion of the two introns (marked by lightning bolt) is depicted in the inset with regions of the reads corresponding to original VTI1A intron in blue and those of TCF7L2 in red. () The protein domain structure of native VTI1A and TCF4-TCF7L2, including the two alternate C-terminal tails of TCF4, are shown. Below are the structures of the fusion protein encoded by the fusion of exon 3 of VTI1A to exon 4 of TCF7L2 identified in CRC-9. Two variants of the fusion are shown as ! data from the NCI-H508 cell line and reveal that variants encoding both the full length (E-tail) and shorter (B-tail) C termini are both expressed (data not shown). () Measurement of the relative expression of the VTI1A-TCF7L2 mRNA in NCI-H508 cells infected with one of two short hairpin RNA constructs targeting the fusion gene relative to expression in a cell infected with control vectors targeting GFP. () Anchorage-independent growth of the NCI-H508 cell line, which expresses VTI1A-TCF7L2, and negative control DLD-1 colorectal adenocarcinoma cells following RNA-interference–mediated knockdown of VTI1A-TCF7L2 compared to control knockdown targeting GFP. Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Adam J Bass & * Michael S Lawrence Affiliations * Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. * Adam J Bass, * Lear E Brace, * Alex H Ramos, * Trevor Pugh, * Roel G Verhaak, * Adam T Boutin, * William G Kaelin, * Nicole Spardy, * William C Hahn, * Shuji Ogino, * Ronald A DePinho, * Lynda Chin, * Levi A Garraway, * Charles S Fuchs & * Matthew Meyerson * Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. * Adam J Bass, * William G Kaelin, * William C Hahn, * Ronald A DePinho, * Levi A Garraway & * Charles S Fuchs * Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. * Adam J Bass, * William C Hahn, * Levi A Garraway & * Matthew Meyerson * Broad Institute, Cambridge, Massachusetts, USA. * Adam J Bass, * Michael S Lawrence, * Alex H Ramos, * Kristian Cibulskis, * Carrie Sougnez, * Douglas Voet, * Gordon Saksena, * Andrey Sivachenko, * Rui Jing, * Melissa Parkin, * Trevor Pugh, * Roel G Verhaak, * Nicolas Stransky, * Jordi Barretina, * William C Hahn, * Yujin Hoshida, * Lynda Chin, * Levi A Garraway, * Stacey Gabriel, * Eric S Lander, * Gad Getz & * Matthew Meyerson * Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel. * Yotam Drier * Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. * David B Solit * Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. * Evi Vakiani * Novartis Institute of Biomedical Research, Cambridge, Massachusetts, USA. * Wenlin Shao, * Yuji Mishina & * Markus Warmuth * Department of Medical Oncology, Hospital Vall d'Hebron, Passeig Vall d'Hebron, Barcelona, Spain. * Jose Jimenez, * Jose Baselga & * Josep Tabernero * Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. * Derek Y Chiang * Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA. * Sabina Signoretti, * Shuji Ogino & * Matthew Meyerson * Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA. * Sabina Signoretti & * Shuji Ogino * Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. * Shuji Ogino & * Charles S Fuchs * Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. * Ronald A DePinho * Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. * Ronald A DePinho & * Lynda Chin * Department of Dermatology, Harvard Medical School, Boston, Massachusetts, USA. * Lynda Chin * Division of Hematology and Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA. * Jose Baselga * Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. * Eric S Lander * Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA. * Eric S Lander Contributions A.J.B., M.S.L., A.H.R., Y.D., K.C., A.S., T.P., R.J., D.V., G.S., R.G.V. and N. Stransky performed computational analysis. J. Barretina, J. Baselga, J.J., J.T., D.B.S., E.V., D.Y.C., W.G.K. and S.S. provided samples for analysis. A.J.B., L.E.B., Y.M. and W.S. performed laboratory experiments. A.T.B., Y.H., M.W., N.S., R.A.D., W.C.H., C.S.F. and S.O. provided expert guidance regarding the analysis. C.S., M.P., L.C., L.A.G., S.G. and E.S.L. supervised and designed the sequencing effort. A.J.B., M.S.L., E.S.L., G.G. and M.M. designed the study, analyzed the data and prepared the manuscript. All coauthors reviewed and commented on the manuscript. Competing financial interests M.M., L.A.G. and E.S.L. are equity-holding founding advisors of Foundation Medicine. M.M. and L.A.G. consult for Novartis. M.M. is also a patent holder on the use of EGFR mutations in lung cancer licensed to Genzyme Genetics. W.S., Y.M. and M.W. are employees of Novartis. Corresponding authors Correspondence to: * Gad Getz or * Matthew Meyerson Author Details * Adam J Bass Search for this author in: * NPG journals * PubMed * Google Scholar * Michael S Lawrence Search for this author in: * NPG journals * PubMed * Google Scholar * Lear E Brace Search for this author in: * NPG journals * PubMed * Google Scholar * Alex H Ramos Search for this author in: * NPG journals * PubMed * Google Scholar * Yotam Drier Search for this author in: * NPG journals * PubMed * Google Scholar * Kristian Cibulskis Search for this author in: * NPG journals * PubMed * Google Scholar * Carrie Sougnez Search for this author in: * NPG journals * PubMed * Google Scholar * Douglas Voet Search for this author in: * NPG journals * PubMed * Google Scholar * Gordon Saksena Search for this author in: * NPG journals * PubMed * Google Scholar * Andrey Sivachenko Search for this author in: * NPG journals * PubMed * Google Scholar * Rui Jing Search for this author in: * NPG journals * PubMed * Google Scholar * Melissa Parkin Search for this author in: * NPG journals * PubMed * Google Scholar * Trevor Pugh Search for this author in: * NPG journals * PubMed * Google Scholar * Roel G Verhaak Search for this author in: * NPG journals * PubMed * Google Scholar * Nicolas Stransky Search for this author in: * NPG journals * PubMed * Google Scholar * Adam T Boutin Search for this author in: * NPG journals * PubMed * Google Scholar * Jordi Barretina Search for this author in: * NPG journals * PubMed * Google Scholar * David B Solit Search for this author in: * NPG journals * PubMed * Google Scholar * Evi Vakiani Search for this author in: * NPG journals * PubMed * Google Scholar * Wenlin Shao Search for this author in: * NPG journals * PubMed * Google Scholar * Yuji Mishina Search for this author in: * NPG journals * PubMed * Google Scholar * Markus Warmuth Search for this author in: * NPG journals * PubMed * Google Scholar * Jose Jimenez Search for this author in: * NPG journals * PubMed * Google Scholar * Derek Y Chiang Search for this author in: * NPG journals * PubMed * Google Scholar * Sabina Signoretti Search for this author in: * NPG journals * PubMed * Google Scholar * William G Kaelin Search for this author in: * NPG journals * PubMed * Google Scholar * Nicole Spardy Search for this author in: * NPG journals * PubMed * Google Scholar * William C Hahn Search for this author in: * NPG journals * PubMed * Google Scholar * Yujin Hoshida Search for this author in: * NPG journals * PubMed * Google Scholar * Shuji Ogino Search for this author in: * NPG journals * PubMed * Google Scholar * Ronald A DePinho Search for this author in: * NPG journals * PubMed * Google Scholar * Lynda Chin Search for this author in: * NPG journals * PubMed * Google Scholar * Levi A Garraway Search for this author in: * NPG journals * PubMed * Google Scholar * Charles S Fuchs Search for this author in: * NPG journals * PubMed * Google Scholar * Jose Baselga Search for this author in: * NPG journals * PubMed * Google Scholar * Josep Tabernero Search for this author in: * NPG journals * PubMed * Google Scholar * Stacey Gabriel Search for this author in: * NPG journals * PubMed * Google Scholar * Eric S Lander Search for this author in: * NPG journals * PubMed * Google Scholar * Gad Getz Contact Gad Getz Search for this author in: * NPG journals * PubMed * Google Scholar * Matthew Meyerson Contact Matthew Meyerson Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Author information * Supplementary information Excel files * Supplementary Table 1 (193K) Non-synonymous Mutations and Insertions/Deletions Identified Within Coding Genes * Supplementary Table 4 (152K) Somatic Rearrangements Identified with dRanger Algorithm PDF files * Supplementary Text and Figures (905K) Supplementary Figures 1 and 2, Supplementary Tables 2, 3 and 5 and Supplementary Note. Additional data
• Genome-wide association study identifies five new schizophrenia loci
  - Nat Genet 43(10):969-976 (2011)
  Nature Genetics | Letter Genome-wide association study identifies five new schizophrenia loci * Stephan Ripke1 * Alan R Sanders2, 3 * Kenneth S Kendler4, 5, 6 * Douglas F Levinson7 * Pamela Sklar1, 8 * Peter A Holmans9, 10 * Dan-Yu Lin11 * Jubao Duan2, 3 * Roel A Ophoff12, 13, 14, 15 * Ole A Andreassen16, 17 * Edward Scolnick18 * Sven Cichon19, 20, 21 * David St. Clair22 * Aiden Corvin23 * Hugh Gurling24 * Thomas Werge25 * Dan Rujescu26 * Douglas H R Blackwood27 * Carlos N Pato28 * Anil K Malhotra29, 30, 31 * Shaun Purcell18 * Frank Dudbridge32 * Benjamin M Neale18 * Lizzy Rossin1 * Peter M Visscher33 * Danielle Posthuma34, 35 * Douglas M Ruderfer1 * Ayman Fanous5, 36, 37 * Hreinn Stefansson38 * Stacy Steinberg38 * Bryan J Mowry39, 40 * Vera Golimbet41 * Marc De Hert42 * Erik G Jönsson43 * István Bitter44 * Olli P H Pietiläinen45, 46 * David A Collier47 * Sarah Tosato48 * Ingrid Agartz16, 49 * Margot Albus50 * Madeline Alexander7 * Richard L Amdur36, 37 * Farooq Amin51, 52 * Nicholas Bass24 * Sarah E Bergen1 * Donald W Black53 * Anders D Børglum54, 55 * Matthew A Brown56 * Richard Bruggeman57 * Nancy G Buccola58 * William F Byerley59, 60 * Wiepke Cahn61 * Rita M Cantor14, 15 * Vaughan J Carr62 * Stanley V Catts63 * Khalid Choudhury24 * C Robert Cloninger64 * Paul Cormican23 * Nicholas Craddock9, 10 * Patrick A Danoy56 * Susmita Datta24 * Lieuwe de Haan65 * Ditte Demontis54 * Dimitris Dikeos66 * Srdjan Djurovic16, 67 * Peter Donnelly68, 69 * Gary Donohoe23 * Linh Duong25 * Sarah Dwyer9, 10 * Anders Fink-Jensen70 * Robert Freedman71 * Nelson B Freimer14 * Marion Friedl26 * Lyudmila Georgieva9, 10 * Ina Giegling26 * Michael Gill23 * Birte Glenthøj72 * Stephanie Godard73 * Marian Hamshere9, 10 * Mark Hansen74 * Thomas Hansen25 * Annette M Hartmann26 * Frans A Henskens75 * David M Hougaard76 * Christina M Hultman77 * Andrés Ingason25 * Assen V Jablensky78 * Klaus D Jakobsen25 * Maurice Jay79, 132 * Gesche Jürgens80 * René S Kahn61 * Matthew C Keller81 * Gunter Kenis82 * Elaine Kenny23 * Yunjung Kim83 * George K Kirov9, 10 * Heike Konnerth26 * Bettina Konte26 * Lydia Krabbendam84 * Robert Krasucki24 * Virginia K Lasseter85, 132 * Claudine Laurent79 * Jacob Lawrence24 * Todd Lencz29, 30, 31 * F Bernard Lerer86 * Kung-Yee Liang87 * Paul Lichtenstein77 * Jeffrey A Lieberman88 * Don H Linszen65 * Jouko Lönnqvist89 * Carmel M Loughland90 * Alan W Maclean27 * Brion S Maher4, 5, 6 * Wolfgang Maier91 * Jacques Mallet92 * Pat Malloy27 * Manuel Mattheisen19, 21, 93 * Morten Mattingsdal16, 94 * Kevin A McGhee27 * John J McGrath39, 40 * Andrew McIntosh27 * Duncan E McLean95 * Andrew McQuillin24 * Ingrid Melle16, 17 * Patricia T Michie96, 97 * Vihra Milanova98 * Derek W Morris23 * Ole Mors55 * Preben B Mortensen99 * Valentina Moskvina9, 10 * Pierandrea Muglia100, 101 * Inez Myin-Germeys84 * Deborah A Nertney39, 40 * Gerald Nestadt85 * Jimmi Nielsen102 * Ivan Nikolov9, 10 * Merete Nordentoft103 * Nadine Norton9, 10 * Markus M Nöthen19, 21 * Colm T O'Dushlaine23 * Ann Olincy71 * Line Olsen25 * F Anthony O'Neill104 * Torben F Ørntoft105, 106 * Michael J Owen9, 10 * Christos Pantelis107 * George Papadimitriou66 * Michele T Pato28 * Leena Peltonen45, 46, 108, 132 * Hannes Petursson109 * Ben Pickard110 * Jonathan Pimm24 * Ann E Pulver85 * Vinay Puri24 * Digby Quested111 * Emma M Quinn23 * Henrik B Rasmussen25 * János M Réthelyi44 * Robert Ribble4, 5, 6 * Marcella Rietschel91, 112 * Brien P Riley4, 5, 6 * Mirella Ruggeri48 * Ulrich Schall97, 113 * Thomas G Schulze112, 114 * Sibylle G Schwab115, 116, 117 * Rodney J Scott118 * Jianxin Shi119 * Engilbert Sigurdsson109, 120 * Jeremy M Silverman8, 121 * Chris C A Spencer68 * Kari Stefansson38 * Amy Strange68 * Eric Strengman12, 13 * T Scott Stroup88 * Jaana Suvisaari89 * Lars Terenius43 * Srinivasa Thirumalai122 * Johan H Thygesen25 * Sally Timm123 * Draga Toncheva124 * Edwin van den Oord125 * Jim van Os84 * Ruud van Winkel42, 82 * Jan Veldink126 * Dermot Walsh127 * August G Wang128 * Durk Wiersma57 * Dieter B Wildenauer115, 129 * Hywel J Williams9, 10 * Nigel M Williams9, 10 * Brandon Wormley4, 5, 6 * Stan Zammit9, 10 * Patrick F Sullivan77, 83, 130, 131 * Michael C O'Donovan9, 10 * Mark J Daly1 * Pablo V Gejman2, 3 * for The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:969–976Year published:(2011)DOI:doi:10.1038/ng.940Received16 February 2011Accepted19 August 2011Published online18 September 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10−11) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected indi! viduals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10−9), ANK3 (rs10994359, P = 2.5 × 10−8) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10−9). View full text Figures at a glance * Figure 1: Manhattan plot for stages 1 and 2. Standard −log10P plot of the study results. For the stage 1 results, 16 regions with one or more SNP achieving P < 10−6 are highlighted in color and labeled with the name of the nearest gene. SNPs selected for stage 2 replication are highlighted, with the resulting combined P value after replication (that is, after incorporation of stage 2 results) indicated by the large diamonds. Blue highlighting indicates SNPs that were less significantly associated after replication, and pink highlighting indicates SNPs that were more significantly associated after replication. * Figure 2: Regional association plots for five new schizophrenia loci. Regional P value plots for each of the five new schizophrenia loci: 1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33. Each plot shows the most associated SNP (key SNP) and its genomic region from the first column of Table 2: stage 1 scan results for each SNP ± 200 kb to the key SNP are shown. On the x axis is the genomic position, and on the y axis is −log10P. Larger SNP symbols indicate higher LD (based on HapMap 3 data) to the key SNP than smaller SNP symbols. Color coding (from red to blue) denotes LD information; see also the legend within the plot. Author information * Author information * Supplementary information Affiliations * Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. * Stephan Ripke, * Pamela Sklar, * Lizzy Rossin, * Douglas M Ruderfer, * Sarah E Bergen & * Mark J Daly * Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, Illinois, USA. * Alan R Sanders, * Jubao Duan & * Pablo V Gejman * Department of Psychiatry and Behavioral Sciences, University of Chicago, Chicago, Illinois, USA. * Alan R Sanders, * Jubao Duan & * Pablo V Gejman * Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA. * Kenneth S Kendler, * Brion S Maher, * Robert Ribble, * Brien P Riley & * Brandon Wormley * Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA. * Kenneth S Kendler, * Ayman Fanous, * Brion S Maher, * Robert Ribble, * Brien P Riley & * Brandon Wormley * Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA. * Kenneth S Kendler, * Brion S Maher, * Robert Ribble, * Brien P Riley & * Brandon Wormley * Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, USA. * Douglas F Levinson & * Madeline Alexander * Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA. * Pamela Sklar & * Jeremy M Silverman * Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK. * Peter A Holmans, * Nicholas Craddock, * Sarah Dwyer, * Lyudmila Georgieva, * Marian Hamshere, * George K Kirov, * Valentina Moskvina, * Ivan Nikolov, * Nadine Norton, * Michael J Owen, * Hywel J Williams, * Nigel M Williams, * Stan Zammit & * Michael C O'Donovan * Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK. * Peter A Holmans, * Nicholas Craddock, * Sarah Dwyer, * Lyudmila Georgieva, * Marian Hamshere, * George K Kirov, * Valentina Moskvina, * Ivan Nikolov, * Nadine Norton, * Michael J Owen, * Hywel J Williams, * Nigel M Williams, * Stan Zammit & * Michael C O'Donovan * Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA. * Dan-Yu Lin * Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. * Roel A Ophoff & * Eric Strengman * Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands. * Roel A Ophoff & * Eric Strengman * University of California at Los Angeles (UCLA) Center for Neurobehavioral Genetics, University of California at Los Angeles, Los Angeles, California, USA. * Roel A Ophoff, * Rita M Cantor & * Nelson B Freimer * Department of Human Genetics, University of California at Los Angeles, Los Angeles, California, USA. * Roel A Ophoff & * Rita M Cantor * Psychiatry Section, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. * Ole A Andreassen, * Ingrid Agartz, * Srdjan Djurovic, * Morten Mattingsdal & * Ingrid Melle * Department of Psychiatry, Oslo University Hospital, Oslo, Norway. * Ole A Andreassen & * Ingrid Melle * Broad Institute, Cambridge, Massachusetts, USA. * Edward Scolnick, * Shaun Purcell & * Benjamin M Neale * Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany. * Sven Cichon, * Manuel Mattheisen & * Markus M Nöthen * Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany. * Sven Cichon * Institute of Human Genetics, University of Bonn, Bonn, Germany. * Sven Cichon, * Manuel Mattheisen & * Markus M Nöthen * Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK. * David St. Clair * Neuropsychiatric Genetics Research Group, Trinity College Dublin, Dublin, Ireland. * Aiden Corvin, * Paul Cormican, * Gary Donohoe, * Michael Gill, * Elaine Kenny, * Derek W Morris, * Colm T O'Dushlaine & * Emma M Quinn * Molecular Psychiatry Laboratory, Research Department of Mental Health Sciences, University College London Medical School, Windeyer Institute of Medical Sciences, London, UK. * Hugh Gurling, * Nicholas Bass, * Khalid Choudhury, * Susmita Datta, * Robert Krasucki, * Jacob Lawrence, * Andrew McQuillin, * Jonathan Pimm & * Vinay Puri * Institute of Biological Psychiatry, Mental Health Center (MHC) Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark. * Thomas Werge, * Linh Duong, * Thomas Hansen, * Andrés Ingason, * Klaus D Jakobsen, * Line Olsen, * Henrik B Rasmussen & * Johan H Thygesen * Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany. * Dan Rujescu, * Marion Friedl, * Ina Giegling, * Annette M Hartmann, * Heike Konnerth & * Bettina Konte * Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK. * Douglas H R Blackwood, * Alan W Maclean, * Pat Malloy, * Kevin A McGhee & * Andrew McIntosh * Keck School of Medicine, University of Southern California, Los Angeles, California, USA. * Carlos N Pato & * Michele T Pato * Department of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of the North Shore-Long Island Jewish Health System, Glen Oaks, New York, USA. * Anil K Malhotra & * Todd Lencz * Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, New York, USA. * Anil K Malhotra & * Todd Lencz * Department of Psychiatry and Behavioral Science, Albert Einstein College of Medicine of Yeshiva University, New York, New York, USA. * Anil K Malhotra & * Todd Lencz * Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK. * Frank Dudbridge * Queensland Statistical Genetics Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia. * Peter M Visscher * Vrije Universiteit (VU), Center for Neurogenomics and Cognitive Research (CNCR), Department of Functional Genomics, Amsterdam, The Netherlands. * Danielle Posthuma * VU Medical Centre, Department of Medical Genomics, Amsterdam, The Netherlands. * Danielle Posthuma * Washington Veteran's Affairs Medical Center, Washington, DC, USA. * Ayman Fanous & * Richard L Amdur * Department of Psychiatry, Georgetown University School of Medicine, Washington, DC, USA. * Ayman Fanous & * Richard L Amdur * deCODE Genetics, Reykjavik, Iceland. * Hreinn Stefansson, * Stacy Steinberg & * Kari Stefansson * Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia. * Bryan J Mowry, * John J McGrath & * Deborah A Nertney * Queensland Centre for Mental Health Research, University of Queensland, Brisbane, Queensland, Australia. * Bryan J Mowry, * John J McGrath & * Deborah A Nertney * Mental Health Research Center, Russian Academy of Medical Sciences, Moscow, Russia. * Vera Golimbet * University Psychiatric Centre, Catholic University Leuven, Kortenberg, Belgium. * Marc De Hert & * Ruud van Winkel * Department of Clinical Neuroscience, Human Brain Informatics (HUBIN) Project, Karolinska Institutet and Hospital, Stockholm, Sweden. * Erik G Jönsson & * Lars Terenius * Semmelweis University, Department of Psychiatry and Psychotherapy, Budapest, Hungary. * István Bitter & * János M Réthelyi * Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. * Olli P H Pietiläinen & * Leena Peltonen * Department of Medical Genetics, University of Helsinki, Helsinki, Finland. * Olli P H Pietiläinen & * Leena Peltonen * Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College, London, UK. * David A Collier * Section of Psychiatry and Clinical Psychology, University of Verona, Verona, Italy. * Sarah Tosato & * Mirella Ruggeri * Department of Research, Diakonhjemmet Hospital, Oslo, Norway. * Ingrid Agartz * State Mental Hospital, Haar, Germany. * Margot Albus * Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia, USA. * Farooq Amin * Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, Atlanta, Georgia, USA. * Farooq Amin * Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. * Donald W Black * Institute of Human Genetics, University of Aarhus, Aarhus, Denmark. * Anders D Børglum & * Ditte Demontis * Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark. * Anders D Børglum & * Ole Mors * University of Queensland Diamantina Institute, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia. * Matthew A Brown & * Patrick A Danoy * University Medical Center Groningen, Department of Psychiatry, University of Groningen, Groningen, The Netherlands. * Richard Bruggeman & * Durk Wiersma * School of Nursing, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA. * Nancy G Buccola * Department of Psychiatry, University of California at San Francisco, San Francisco, California, USA. * William F Byerley * NCIRE (Northern California Institute for Research and Education), San Francisco, California, USA. * William F Byerley * Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands. * Wiepke Cahn & * René S Kahn * School of Psychiatry, University of New South Wales and Schizophrenia Research Institute, Sydney, New South Wales, Australia. * Vaughan J Carr * Department of Psychiatry, University of Queensland, Royal Brisbane Hospital, Brisbane, Australia. * Stanley V Catts * Department of Psychiatry, Washington University, St. Louis, Missouri, USA. * C Robert Cloninger * Academic Medical Centre, University of Amsterdam, Department of Psychiatry, Amsterdam, The Netherlands. * Lieuwe de Haan & * Don H Linszen * Department of Psychiatry, University of Athens Medical School, Athens, Greece. * Dimitris Dikeos & * George Papadimitriou * Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. * Srdjan Djurovic * Wellcome Trust Centre for Human Genetics, Oxford, UK. * Peter Donnelly, * Chris C A Spencer & * Amy Strange * Department of Statistics, University of Oxford, Oxford, UK. * Peter Donnelly * Mental Health Center Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark. * Anders Fink-Jensen * Department of Psychiatry, University of Colorado Denver, Aurora, Colorado, USA. * Robert Freedman & * Ann Olincy * Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Mental Health Center Glostrup, Copenhagen University Hospital, Glostrup, Denmark. * Birte Glenthøj * INSERM, Institut de Myologie, Hôpital de la Pitié-Salpêtrière, Paris, France. * Stephanie Godard * Illumina, Inc., La Jolla, California, USA. * Mark Hansen * School of Electrical Engineering and Computing Science, University of Newcastle, Newcastle, New South Wales, Australia. * Frans A Henskens * Section of Neonatal Screening and Hormones, Department of Clinical Chemistry and Immunology, The State Serum Institute, Copenhagen, Denmark. * David M Hougaard * Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. * Christina M Hultman, * Paul Lichtenstein & * Patrick F Sullivan * Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth, Western Australia, Australia. * Assen V Jablensky * Department of Child and Adolescent Psychiatry, Pierre and Marie Curie Faculty of Medicine, Paris, France. * Maurice Jay & * Claudine Laurent * Department of Clinical Pharmacology, Bispebjerg University Hospital, Copenhagen, Denmark. * Gesche Jürgens * Department of Psychology, University of Colorado, Boulder, Boulder, Colorado, USA. * Matthew C Keller * Department of Psychiatry and Psychology, School of Mental Health and Neuroscience, European Graduate School of Neuroscience (EURON), South Limburg Mental Health Research and Teaching Network (SEARCH), Maastricht University Medical Centre, Maastricht, The Netherlands. * Gunter Kenis & * Ruud van Winkel * Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. * Yunjung Kim & * Patrick F Sullivan * Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, Maastricht, The Netherlands. * Lydia Krabbendam, * Inez Myin-Germeys & * Jim van Os * Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. * Virginia K Lasseter, * Gerald Nestadt & * Ann E Pulver * Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. * F Bernard Lerer * Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA. * Kung-Yee Liang * Department of Psychiatry, Columbia University, New York, New York, USA. * Jeffrey A Lieberman & * T Scott Stroup * Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland. * Jouko Lönnqvist & * Jaana Suvisaari * Schizophrenia Research Institute, Sydney and Centre for Brain and Mental Health Research, University of Newcastle, Newcastle, New South Wales, Australia. * Carmel M Loughland * Department of Psychiatry, University of Bonn, Bonn, Germany. * Wolfgang Maier & * Marcella Rietschel * Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, Centre National de la Recherche Scientifique, Hôpital de la Pitié Salpêtrière, Paris, France. * Jacques Mallet * Institute of Medical Biometry, Informatics and Epidemiology (IMBIE), University of Bonn, Bonn, Germany. * Manuel Mattheisen * Department of Research, Sørlandet Hospital, Kristiansand, Norway. * Morten Mattingsdal * Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, Queensland, Australia. * Duncan E McLean * Functional NeuroImaging Laboratory, School of Psychology, University of Newcastle, Sydney, New South Wales, Australia. * Patricia T Michie * Schizophrenia Research Institute, Sydney, New South Wales, Australia. * Patricia T Michie & * Ulrich Schall * Department of Psychiatry, First Psychiatric Clinic, Alexander University Hospital, Sofia, Bulgaria. * Vihra Milanova * National Centre for Register-Based Research, University of Aarhus, Aarhus, Denmark. * Preben B Mortensen * Department of Psychiatry, University of Toronto, Toronto, Canada. * Pierandrea Muglia * NeuroSearch A/S, Ballerup, Denmark. * Pierandrea Muglia * Unit for Psychiatric Research, Aalborg Psychiatric Hospital, Aalborg, Denmark. * Jimmi Nielsen * Psychiatric Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark. * Merete Nordentoft * Department of Psychiatry, Queens University, Belfast, Ireland. * F Anthony O'Neill * ARoS Applied Biotechnology A/S, Skejby, Denmark. * Torben F Ørntoft * Department of Molecular Medicine, Aarhus University Hospital, Skejby, Denmark. * Torben F Ørntoft * Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Melbourne, Victoria, Australia. * Christos Pantelis * Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. * Leena Peltonen * Department of Psychiatry, National University Hospital, Reykjavik, Iceland. * Hannes Petursson & * Engilbert Sigurdsson * Strathclyde Institute of Pharmacy and Biomedical Sciences, The John Arbuthnott Building, University of Strathclyde, Glasgow, UK. * Ben Pickard * Department of Psychiatry, University of Oxford, Warneford Hospital, Headington, Oxford, UK. * Digby Quested * Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany. * Marcella Rietschel & * Thomas G Schulze * Priority Centre for Brain and Mental Health Research, University of Newcastle, Sydney, New South Wales, Australia. * Ulrich Schall * Department of Psychiatry and Psychotherapy, Georg-August-University, Göttingen, Germany. * Thomas G Schulze * School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Western Australia, Australia. * Sibylle G Schwab & * Dieter B Wildenauer * Department of Psychiatry, University of Erlangen-Nuremberg, Erlangen, Germany. * Sibylle G Schwab * Centre for Medical Research, Western Australian Institute for Medical Research, University of Western Australia, Perth, Western Australia, Australia. * Sibylle G Schwab * Centre for Information Based Medicine, University of Newcastle, Hunter Medical Research Institute, Newcastle and Schizophrenia Research Institute, Sydney, New South Wales, Australia. * Rodney J Scott * Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA. * Jianxin Shi * Department of Psychiatry, University of Iceland, Reykjavik, Iceland. * Engilbert Sigurdsson * Department of Psychiatry, Veterans Affairs Medical Center, New York, New York, USA. * Jeremy M Silverman * West Berkshire National Health Service (NHS) Trust, Reading, UK. * Srinivasa Thirumalai * Mental Health Center Frederiksberg, Copenhagen University Hospital, Copenhagen, Denmark. * Sally Timm * Department of Medical Genetics, University Hospital Maichin Dom, Sofia, Bulgaria. * Draga Toncheva * Department of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, USA. * Edwin van den Oord * Rudolf Magnus Institute of Neuroscience, Department of Neurology, Universitair Medisch Centrum (UMC) Utrecht, Utrecht, The Netherlands. * Jan Veldink * The Health Research Board, Dublin, Ireland. * Dermot Walsh * Mental Health Center Amager, Copenhagen University Hospital, Copenhagen, Denmark. * August G Wang * Centre for Clinical Research in Neuropsychiatry, Graylands Hospital, Mt Claremont, Western Australia, Australia. * Dieter B Wildenauer * Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. * Patrick F Sullivan * Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. * Patrick F Sullivan * Deceased. * Maurice Jay, * Virginia K Lasseter & * Leena Peltonen Consortia * The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium * Stephan Ripke, * Alan R Sanders, * Kenneth S Kendler, * Douglas F Levinson, * Pamela Sklar, * Peter A Holmans, * Dan-Yu Lin, * Jubao Duan, * Roel A Ophoff, * Ole A Andreassen, * Edward Scolnick, * Sven Cichon, * David St. Clair, * Aiden Corvin, * Hugh Gurling, * Thomas Werge, * Dan Rujescu, * Douglas H R Blackwood, * Carlos N Pato, * Anil K Malhotra, * Shaun Purcell, * Frank Dudbridge, * Benjamin M Neale, * Lizzy Rossin, * Peter M Visscher, * Danielle Posthuma, * Douglas M Ruderfer, * Ayman Fanous, * Hreinn Stefansson, * Stacy Steinberg, * Bryan J Mowry, * Vera Golimbet, * Marc De Hert, * Erik G Jönsson, * István Bitter, * Olli P H Pietiläinen, * David A Collier, * Sarah Tosato, * Ingrid Agartz, * Margot Albus, * Madeline Alexander, * Richard L Amdur, * Farooq Amin, * Nicholas Bass, * Sarah E Bergen, * Donald W Black, * Anders D Børglum, * Matthew A Brown, * Richard Bruggeman, * Nancy G Buccola, * William F Byerley, * Wiepke Cahn, * Rita M Cantor, * Vaughan J Carr, * Stanley V Catts, * Khalid Choudhury, * C Robert Cloninger, * Paul Cormican, * Nicholas Craddock, * Patrick A Danoy, * Susmita Datta, * Lieuwe de Haan, * Ditte Demontis, * Dimitris Dikeos, * Srdjan Djurovic, * Peter Donnelly, * Gary Donohoe, * Linh Duong, * Sarah Dwyer, * Anders Fink-Jensen, * Robert Freedman, * Nelson B Freimer, * Marion Friedl, * Lyudmila Georgieva, * Ina Giegling, * Michael Gill, * Birte Glenthøj, * Stephanie Godard, * Marian Hamshere, * Mark Hansen, * Thomas Hansen, * Annette M Hartmann, * Frans A Henskens, * David M Hougaard, * Christina M Hultman, * Andrés Ingason, * Assen V Jablensky, * Klaus D Jakobsen, * Maurice Jay, * Gesche Jürgens, * René S Kahn, * Matthew C Keller, * Gunter Kenis, * Elaine Kenny, * Yunjung Kim, * George K Kirov, * Heike Konnerth, * Bettina Konte, * Lydia Krabbendam, * Robert Krasucki, * Virginia K Lasseter, * Claudine Laurent, * Jacob Lawrence, * Todd Lencz, * F Bernard Lerer, * Kung-Yee Liang, * Paul Lichtenstein, * Jeffrey A Lieberman, * Don H Linszen, * Jouko Lönnqvist, * Carmel M Loughland, * Alan W Maclean, * Brion S Maher, * Wolfgang Maier, * Jacques Mallet, * Pat Malloy, * Manuel Mattheisen, * Morten Mattingsdal, * Kevin A McGhee, * John J McGrath, * Andrew McIntosh, * Duncan E McLean, * Andrew McQuillin, * Ingrid Melle, * Patricia T Michie, * Vihra Milanova, * Derek W Morris, * Ole Mors, * Preben B Mortensen, * Valentina Moskvina, * Pierandrea Muglia, * Inez Myin-Germeys, * Deborah A Nertney, * Gerald Nestadt, * Jimmi Nielsen, * Ivan Nikolov, * Merete Nordentoft, * Nadine Norton, * Markus M Nöthen, * Colm T O'Dushlaine, * Ann Olincy, * Line Olsen, * F Anthony O'Neill, * Torben F Ørntoft, * Michael J Owen, * Christos Pantelis, * George Papadimitriou, * Michele T Pato, * Leena Peltonen, * Hannes Petursson, * Ben Pickard, * Jonathan Pimm, * Ann E Pulver, * Vinay Puri, * Digby Quested, * Emma M Quinn, * Henrik B Rasmussen, * János M Réthelyi, * Robert Ribble, * Marcella Rietschel, * Brien P Riley, * Mirella Ruggeri, * Ulrich Schall, * Thomas G Schulze, * Sibylle G Schwab, * Rodney J Scott, * Jianxin Shi, * Engilbert Sigurdsson, * Jeremy M Silverman, * Chris C A Spencer, * Kari Stefansson, * Amy Strange, * Eric Strengman, * T Scott Stroup, * Jaana Suvisaari, * Lars Terenius, * Srinivasa Thirumalai, * Johan H Thygesen, * Sally Timm, * Draga Toncheva, * Edwin van den Oord, * Jim van Os, * Ruud van Winkel, * Jan Veldink, * Dermot Walsh, * August G Wang, * Durk Wiersma, * Dieter B Wildenauer, * Hywel J Williams, * Nigel M Williams, * Brandon Wormley, * Stan Zammit, * Patrick F Sullivan, * Michael C O'Donovan, * Mark J Daly & * Pablo V Gejman Contributions The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium (PGC): : P.V.G. M.J.D. K.S.K. S.R., M.J.D., P.A.H., D.-Y.L., S.P., F.D., B.M.N., L.R., P.M.V., D.P., D.M.R. P.V.G. (primary), M.J.D. (primary), A.R.S. (primary), S.R. (primary), M.C.O. (primary), K.S.K., D.F.L., P.S., P.A.H., P.F.S. (primary), D.-Y.L., J.D., R.A.O., O.A.A., E. Scolnick. K.S.K., A.F., A.C., R.L.A. M.C.O., N.C., P.A.H., M. Hamshere, H.J.W., V. Moskvina, S. Dwyer, L.G., S.Z., M.J.O. P.F.S., D.-Y.L., E.v.d.O., Y.K., T.S.S., J.A.L. D.St.C. G.K.K., M.C.O., P.A.H., L.G., I.N., H.J.W., D.T., V. Milanova, M.J.O. D.W.M., C.T.O., E.K., E.M.Q., M.G., A.C. D.H.R.B., K.A.M., B.P., P. Malloy, A.W.M., A. McIntosh. A. McQuillin, K.C., S. Datta, J.P., S. Thirumalai, V.P., R.K., J. Lawrence, D.Q., N.B., H.G. M.T.P., C.N.P., A.F. C.M.H., P.L., S.E.B., S.P., E. Scolnick, P.S., P.F.S. J. Shi, D.F.L., J.D., A.R.S., M.C.K., B.J.M., A.O., F.A., C.R.C., J.M.S., N.G.B., W.FB., D.W.B., K.S.K., ! R.F., P.V.G. S.C., M. Rietschel, M.M.N., W.M., T.G.S., M. Mattheisen. T.H., A.I., K.D.J., L.D., G.J., H.B.R., B.G., J.N., S. Timm, L.O., A.G.W., A.F.-J., J.H.T., T.W. I.G., A.M.H., H.K., M.F., B.K., P. Muglia, D.R. S. Djurovic, M. Mattingsdal, I.A., I.M., O.A.A. R.A.O., R.M.C., N.B.F., R.S.K., D.H.L., J.v.O., D. Wiersma, R.B., W.C., L.d.H., L.K., I.M.-G., E. Strengman. A.K.M., T.L. P.A.H., B.P.R., A.E.P., M.J.O., D.B.W., P.V.G., B.J.M., C.L., K.S.K., G.N., N.M.W., S.G.S., A.R.S., M. Hansen, D.A.N., J.M., B.W., V.K.L., M.C.O., J.D., M. Albus, M. Alexander, S.G., R.R., K.-Y.L., N.N., W.M., G.P., D. Walsh, M.J., F.A.O., F.B.L., D. Dikeos, J.M.S., D.F.L. A.D.B., D. Demontis, P.B.M., D.M.H., T.FØ., O.M. O.M., M.N., A.D.B. R.v.W., G.K., M.D.H., J.V. H.S., S.S., E. Sigurdsson, H.P., K.S. D.A.C. L.P., O.P.H.P., J. Suvisaari, J. önnqvist. I.B., J.M.R. M. Ruggeri, S. Tosato. V.G. E.G.J., I.A., L.T. B.J.M., M.A.B., P.A.D., J.J.M., D.E.M. B.J.M., V.J.C., R.J.S., S.V.C., F.A.H.,! A.V.J., C.M.L., P.T.M., C.P., U.S. A.C., D.W.M., P.C., B.S.M.! , C.T.O., G.D., F.A.O., M.G., K.S.K., B.P.R., ISGC (see the Acknowledgments in theSupplementary Not for additional contributors not listed above). P.D. (Chair of Management Committee; Data and Analysis Group), C.C.A.S. (Data and Analysis Group; Publications Committee), A.S. (Data and Analysis Group), WTCCC2 (see Acknowledgments in theSupplementary Not for additional contributors not listed above). All authors contributed to the current version of the paper Stephan Ripke1, Alan R Sanders2,3, Kenneth S Kendler4,5,6, Douglas F Levinson7, Pamela Sklar1,8, Peter A Holmans9,10, Dan-Yu Lin11, Jubao Duan2,3, Roel A Ophoff12,13,14,15, Ole A Andreassen16,17, Edward Scolnick18, Sven Cichon19,20,21, David St. Clair22, Aiden Corvin23, Hugh Gurling24, Thomas Werge25, Dan Rujescu26, Douglas H R Blackwood27, Carlos N Pato28, Anil K Malhotra29,30,31, Shaun Purcell18, Frank Dudbridge32, Benjamin M Neale18, Lizzy Rossin1, Peter M Visscher33, Danielle Posthuma34,35, Douglas M Ruderfer1, Ayman Fanous5,36,37, Hreinn Stefansson38, Stacy Steinberg38, Bryan J Mowry39,40, Vera Golimbet41, Marc De Hert42, Erik G Jönsson43, István Bitter44, Olli P H Pietiläinen45,46, David A Collier47, Sarah Tosato48, Ingrid Agartz16,49, Margot Albus50, Madeline Alexander7, Richard L Amdur36,37, Farooq Amin51,52, Nicholas Bass24, Sarah E Bergen1, Donald W Black53, Anders D Børglum54,55, Matthew A Brown56, Richard Bruggeman57, Nancy G Buccola58, William F Byerley59,60! , Wiepke Cahn61, Rita M Cantor14,15, Vaughan J Carr62, Stanley V Catts63, Khalid Choudhury24, C Robert Cloninger64, Paul Cormican23, Nicholas Craddock9,10, Patrick A Danoy56, Susmita Datta24, Lieuwe de Haan65, Ditte Demontis54, Dimitris Dikeos66, Srdjan Djurovic16,67, Peter Donnelly68,69, Gary Donohoe23, Linh Duong25, Sarah Dwyer9,10, Anders Fink-Jensen70, Robert Freedman71, Nelson B Freimer14, Marion Friedl26, Lyudmila Georgieva9,10, Ina Giegling26, Michael Gill23, Birte Glenthøj72, Stephanie Godard73, Marian Hamshere9,10, Mark Hansen74, Thomas Hansen25, Annette M Hartmann26, Frans A Henskens75, David M Hougaard76, Christina M Hultman77, Andrés Ingason25, Assen V Jablensky78, Klaus D Jakobsen25, Maurice Jay79,132, Gesche Jürgens80, René S Kahn61, Matthew C Keller81, Gunter Kenis82, Elaine Kenny23, Yunjung Kim83, George K Kirov9,10, Heike Konnerth26, Bettina Konte26, Lydia Krabbendam84, Robert Krasucki24, Virginia K Lasseter85,132, Claudine Laurent79, Jacob Lawrence24, ! Todd Lencz29,30,31, F Bernard Lerer86, Kung-Yee Liang87, Paul ! Lichtenstein77, Jeffrey A Lieberman88, Don H Linszen65, Jouko Lönnqvist89, Carmel M Loughland90, Alan W Maclean27, Brion S Maher4,5,6, Wolfgang Maier91, Jacques Mallet92, Pat Malloy27, Manuel Mattheisen19,21,93, Morten Mattingsdal16,94, Kevin A McGhee27, John J McGrath39,40, Andrew McIntosh27, Duncan E McLean95, Andrew McQuillin24, Ingrid Melle16,17, Patricia T Michie96,97, Vihra Milanova98, Derek W Morris23, Ole Mors55, Preben B Mortensen99, Valentina Moskvina9,10, Pierandrea Muglia100,101, Inez Myin-Germeys84, Deborah A Nertney39,40, Gerald Nestadt85, Jimmi Nielsen102, Ivan Nikolov9,10, Merete Nordentoft103, Nadine Norton9,10, Markus M Nöthen19,21, Colm T O'Dushlaine23, Ann Olincy71, Line Olsen25, F Anthony O'Neill104, Torben F Ørntoft105,106, Michael J Owen9,10, Christos Pantelis107, George Papadimitriou66, Michele T Pato28, Leena Peltonen45,46,108,132, Hannes Petursson109, Ben Pickard110, Jonathan Pimm24, Ann E Pulver85, Vinay Puri24, Digby Quested111, Emma M Quinn23! , Henrik B Rasmussen25, János M Réthelyi44, Robert Ribble4,5,6, Marcella Rietschel91,112, Brien P Riley4,5,6, Mirella Ruggeri48, Ulrich Schall97,113, Thomas G Schulze112,114, Sibylle G Schwab115,116,117, Rodney J Scott118, Jianxin Shi119, Engilbert Sigurdsson109,120, Jeremy M Silverman8,121, Chris C A Spencer68, Kari Stefansson38, Amy Strange68, Eric Strengman12,13, T Scott Stroup88, Jaana Suvisaari89, Lars Terenius43, Srinivasa Thirumalai122, Johan H Thygesen25, Sally Timm123, Draga Toncheva124, Edwin van den Oord125, Jim van Os84, Ruud van Winkel42,82, Jan Veldink126, Dermot Walsh127, August G Wang128, Durk Wiersma57, Dieter B Wildenauer115,129, Hywel J Williams9,10, Nigel M Williams9,10, Brandon Wormley4,5,6, Stan Zammit9,10, Patrick F Sullivan77,83,130,131, Michael C O'Donovan9,10, Mark J Daly1 & Pablo V Gejman2,3 Competing financial interests Eli Lilly funded portions of the genotyping for CATIE and TOP. P.F.S. received research funding from Eli Lilly in connection with CATIE. T.S.S. received research funding from Eli Lilly and consulting fees from Janssen Pharmaceutica, GlaxoSmithKline and Bristol-Myers Squibb. J.A.L. received research funding from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Janssen Pharmaceutica and Pfizer and consulting and educational fees from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Novartis, Pfizer and Solvay. D.St.C. received research funding from GlaxoSmithKline and Generation Scotland, Genetics Health Initiative. F.A. received funds from Pfizer, Organon and the Foundation for the National Institutes of Health. D.W.B. has received research support from Shire and Forest, has been on the speakers' bureau for Pfizer and has received consulting honoraria from Forest and Jazz. T.W. has! received consulting and lecture fees from H. Lundbeck A/S. O.A.A. has received Speaker's honorarium from AstraZeneca, Janssen, Bristol-Myers Squibb and GlaxoSmithKline. I.M. has received a Speaker's honorarium from Janssen and AstraZeneca. A.K.M. has received consulting fees or honoraria from Eli Lilly & Company, Janssen Pharmaceutica, Merck, Bristol-Meyers Squibb, Pfizer, PGxHealth (a division of Clinical Data, Inc.), Roche Diagnostics and Vanda Pharmaceuticals and has received research support from Eli Lilly & Company. T.L. has received consulting fees or honoraria from Merck, Eli Lilly & Company, Golden Helix, Inc., InforMed Insights and PGxHealth (a division of Clinical Data, Inc.). I.B. has been an advisory board member, consultant and lecturer for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, EGIS, Janssen, H. Lundbeck A/S, Novartis, Pfizer, Richter and Schering-Plough and received a grant for an investigator-initiated study from H. Lundbeck A/S. J.J.M. has received ! consulting and speaker's fees from Johnson & Johnson, Schering! -Plough and Eli Lilly. C.P. has received grant support from Janssen-Cilag, Eli Lilly, Hospira (Mayne) and AstraZeneca, provided consultancy to Janssen-Cilag, Eli Lilly, Hospira (Mayne), AstraZeneca, Pfizer and Schering-Plough and has undertaken investigator-initiated studies supported by Eli Lilly, Hospira, Janssen Cilag and AstraZeneca. The Denmark-Aarhus group (The GEMS Stud with principal investigators A.D.B., O.M. and P.B.M.) received research funding from H. Lundbeck A/S. E.G.J. has served as an unpaid consultant for Eli Lilly. Corresponding author Correspondence to: * Pablo V Gejman Author Details * Stephan Ripke Search for this author in: * NPG journals * PubMed * Google Scholar * Alan R Sanders Search for this author in: * NPG journals * PubMed * Google Scholar * Kenneth S Kendler Search for this author in: * NPG journals * PubMed * Google Scholar * Douglas F Levinson Search for this author in: * NPG journals * PubMed * Google Scholar * Pamela Sklar Search for this author in: * NPG journals * PubMed * Google Scholar * Peter A Holmans Search for this author in: * NPG journals * PubMed * Google Scholar * Dan-Yu Lin Search for this author in: * NPG journals * PubMed * Google Scholar * Jubao Duan Search for this author in: * NPG journals * PubMed * Google Scholar * Roel A Ophoff Search for this author in: * NPG journals * PubMed * Google Scholar * Ole A Andreassen Search for this author in: * NPG journals * PubMed * Google Scholar * Edward Scolnick Search for this author in: * NPG journals * PubMed * Google 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• Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4
  - Nat Genet 43(10):977-983 (2011)
  Nature Genetics | Letter Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4 * Psychiatric GWAS Consortium Bipolar Disorder Working Group * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:977–983Year published:(2011)DOI:doi:10.1038/ng.943Received28 March 2011Accepted23 August 2011Published online18 September 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 × 10−7). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will con! firm many additional loci. View full text Author information * Author information * Supplementary information Affiliations * Division of Psychiatric Genomics, Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA. * Pamela Sklar * Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. * Pamela Sklar, * Stephan Ripke, * Mark Daly, * Manuel A Ferreira, * Colm O'Dushlaine, * Roy Perlis, * Soumya Raychaudhuri, * Douglas Ruderfer, * Phil L Hyoun, * Jordan W Smoller, * Sarah E Bergen & * Shaun M Purcell * Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. * Stephan Ripke, * Mark Daly, * Manuel A Ferreira, * Colm O'Dushlaine, * Roy Perlis, * Soumya Raychaudhuri, * Douglas Ruderfer, * Jordan W Smoller, * Kim Chambert, * Jennifer Moran, * Ed Scolnick, * Sarah E Bergen & * Shaun M Purcell * Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA. * Laura J Scott, * Matthew Flickinger, * Weihua Guan, * Phoenix Kwan & * Michael Boehnke * Institute of Clinical Medicine, European Network of Bipolar Research Expert Centers (ENBREC) Group, University of Oslo, Oslo, Norway. * Ole A Andreassen, * Morten Mattingsdal, * Srdjan Djurovic & * Ingrid Melle * Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. * Ole A Andreassen & * Ingrid Melle * Institute of Human Genetics, University of Bonn, Bonn, Germany. * Sven Cichon, * Thomas W Mühleisen, * Franziska A Degenhardt, * Manuel Mattheisen, * Johannes Schumacher, * Peter Propping & * Markus M Nöthen * Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany. * Sven Cichon, * Thomas W Mühleisen, * Franziska A Degenhardt & * Markus M Nöthen * Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany. * Sven Cichon * Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff, UK. * Nick Craddock, * Peter A Holmans, * Marian L Hamshere, * Katherine Gordon-Smith, * Christine Fraser, * Elaine K Green, * Detelina Grozeva, * Ian R Jones, * George Kirov, * Valentina Moskvina, * Ivan Nikolov, * Michael C O'Donovan & * Michael J Owen * Department of Biochemistry and Molecular Biology, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA. * Howard J Edenberg * Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA. * John I Nurnberger Jr, * Tatiana Foroud & * Daniel L Koller * Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA. * John I Nurnberger Jr * Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health Mannheim, University of Heidelberg, Mannheim, Germany. * Marcella Rietschel, * Thomas G Schulze, * René Breuer, * Sandra Meier, * Jana Strohmaier & * Stephanie H Witt * Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK. * Douglas Blackwood, * Kevin McGhee, * Andrew McIntosh, * Alan W McLean, * Walter J Muir & * Benjamin S Pickard * Medical Genetics Section, University of Edinburgh Molecular Medicine Centre, Western General Hospital, Edinburgh, UK. * Douglas Blackwood, * Kevin McGhee, * Andrew McIntosh, * Alan W McLean, * Walter J Muir & * Benjamin S Pickard * Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland. * Aiden Corvin, * Michael Gill, * Derek Morris & * Emma Quinn * Sorlandet Hospital HF, Kristiansand, Norway. * Morten Mattingsdal * Molecular Psychiatry Laboratory, Research Department of Mental Health Sciences, University College London, Rockefeller Building, London, UK. * Andrew McQuillin, * Adebayo Anjorin, * Nick Bass, * Hugh Gurling, * Radhika Kandaswamy & * Jacob Lawrence * Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany. * Thomas F Wienker, * Manuel Mattheisen & * Michael Steffens * London School of Hygiene and Tropical Medicine, University of London, London, UK. * Frank Dudbridge * Biostatistics and Bioinformatics Unit, Cardiff University School of Medicine, Cardiff, UK. * Peter A Holmans * Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA. * Danyu Lin * Department of Human Genetics, Department of Psychiatry, Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan, USA. * Margit Burmeister & * Jun Li * Department of Psychiatry, University of California San Diego, La Jolla, California, USA. * Tiffany A Greenwood, * Caroline M Nievergelt, * Rebecca McKinney, * Paul D Shilling & * John R Kelsoe * Neurosciences Centre of Excellence in Drug Discovery, GlaxoSmithKline Research and Development, Verona, Italy. * Marian L Hamshere, * Pierandrea Muglia, * Federica Tozzi & * Valentina Moskvina * The Scripps Translational Science Institute and Scripps Health, La Jolla, California, USA. * Erin N Smith & * Cinnamon S Bloss * Department of Mental Health, Johns Hopkins University and Hospital, Baltimore, Maryland, USA. * Peter P Zandi, * James B Potash & * Pamela B Mahon * The Scripps Translational Science Institute and The Scripps Research Institute, La Jolla, California, USA. * Nicholas J Schork * Department of Psychiatry, University of Chicago, Chicago, Illinois, USA. * Elliot S Gershon, * Chunyu Liu & * Judith A Badner * Rush University Medical Center, Chicago, Illinois, USA. * William A Scheftner * Department of Psychiatry and Behavioral Sciences, Howard University College of Medicine, Washington, DC, USA. * William B Lawson, * Evaristus A Nwulia & * Maria Hipolito * Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA. * William Coryell * Washington University School of Medicine, St. Louis, Missouri, USA. * John Rice * Department of Psychiatry, University of California San Francisco School of Medicine, San Francisco, California, USA. * William Byerley * National Institute of Mental Health, US National Institutes of Health, Bethesda, Maryland, USA. * Francis J McMahon & * Thomas G Schulze * Department of Psychiatry, University Göttingen, Göttingen, Germany. * Thomas G Schulze * Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA. * Wade Berrettini & * Falk W Lohoff * Department of Psychiatry, University of Michigan, Ann Arbor, Michigan, USA. * Melvin G McInnis, * Sebastian Zöllner & * Peng Zhang * The Translational Genomics Research Institute, Phoenix, Arizona, USA. * David W Craig & * Szabocls Szelinger * Portland Veterans Affairs Medical Center, Portland, Oregon, USA. * Thomas B Barrett * Social, Genetic and Developmental Psychiatry (SGDP) Centre, The Institute of Psychiatry, King's College London, De Crespigny Park Denmark Hill, London, UK. * Anne Farmer, * Peter McGuffin, * Gerome Breen, * David A Collier, * Amanda Elkin & * Richard Williamson * Molecular Neuropsychiatry and Development Laboratory, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. * John Strauss & * John B Vincent * Department of Biostatistics, Princess Margaret Hospital, Toronto, Ontario, Canada. * Wei Xu * Psychiatric Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. * James L Kennedy * University of Dundee School of Medicine, Nethergate, Dundee, UK. * Keith Matthews, * Allan H Young & * I Nicol Ferrier * School of Neurology, Neurobiology and Psychiatry, Royal Victoria Infirmary, Newcastle upon Tyne, UK. * Richard Day * Queensland Institute of Medical Research, Brisbane, Australia. * Manuel A Ferreira, * Nick Martin & * Grant W Montgomery * HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA. * Devin Absher & * Richard M Myers * Department of Psychiatry and Human Behavior, University of California, Irvine, California, USA. * Robert C Thompson & * William E Bunney * Department of Psychiatry, Weill Medical College, Cornell University, New York, New York, USA. * Fan Guo Meng & * Jack D Barchas * Psychiatry and Behavioral Science, Stanford University School of Medicine, Palo Alto, California, USA. * Alan F Schatzberg * Department of Psychiatry and Behavioral Sciences, Center for Neuroscience, University of California, Davis, California, USA. * Edward G Jones * Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan, USA. * Stanley J Watson & * Huda Akil * Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. * Srdjan Djurovic * Department of Psychiatry, St. Olavs Hospital, Trondheim, Norway. * Gunnar Morken * Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway. * Gunnar Morken * Department of Psychiatry, University of Bonn, Bonn, Germany. * Wolfgang Maier * University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, UK. * Gerome Breen & * David St. Clair * Department of Psychiatry, School of Clinical and Experimental Medicine, Birmingham University, Birmingham, UK. * Sian Caesar, * Katherine Gordon-Smith & * Lisa Jones * University of British Columbia (UBC) Institute of Mental Health, Vancouver, British Columbia, Canada. * Allan H Young * deCODE genetics, Reykjavík, Iceland. * Kari Stefansson, * Hreinn Stefansson, * Þorgeir Þorgeirsson, * Stacy Steinberg & * Ómar Gustafsson * Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. * Vishwajit Nimgaonkar * Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. * Christina Hultman, * Mikael Landén & * Paul Lichtenstein * Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden. * Mikael Landén & * Niklas Langstrom * Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA. * Patrick Sullivan * Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. * Martin Schalling, * Urban Osby & * Louise Frisén * Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. * Lena Backlund * INSERM, U955, Psychiatrie Génétique, Créteil, France. * Stéphane Jamain, * Marion Leboyer, * Bruno Etain & * Frank Bellivier * Université Paris Est, Faculté de Médecine, Créteil, France. * Stéphane Jamain, * Marion Leboyer, * Bruno Etain & * Frank Bellivier * Assistance Publique–Hôpitaux de Paris (AP-HP), Hôpital H. Mondor–A. Chenevier, Département de Psychiatrie, Créteil, France. * Stéphane Jamain, * Marion Leboyer, * Bruno Etain & * Frank Bellivier * ENBREC group, Fondation Fondamental, Créteil, France. * Stéphane Jamain, * Marion Leboyer, * Bruno Etain & * Frank Bellivier * Division of Psychiatry, Landspitali University Hospital, University of Iceland, Reykjavik, Iceland. * Hannes Petursson & * Engilbert Sigur∂sson * Max Planck Institute of Psychiatry, Munich, Germany. * Bertram Müller-Mysok & * Susanne Lucae * Psychiatric Center Nordbaden, Wiesloch, Germany. * Markus Schwarz * Prince of Wales Medical Institute, Sydney, Australia. * Peter R Schofield * University of New South Wales, Sydney, Australia. * Peter R Schofield * Centre National de Génotypage, Evry, France. * Mark Lathrop * Therapeia, Reykjavik, Iceland. * Högni Óskarsson * Department of Psychiatry and Psychotherapy, ENBREC Group, University Hospital Carl Gustav Carus, Dresden, Germany. * Michael Bauer * School of Psychiatry, University of New South Wales and Black Dog Institute, Sydney, New South Wales, Australia. * Adam Wright & * Philip B Mitchell * Department of Clinical and Developmental Psychology, Institute of Psychology, University of Tubingen, Tubingen, Germany. * Martin Hautzinger * Department of Psychiatry, University of Würzburg, Würzburg, Germany. * Andreas Reif * Department of Psychiatry, Special Treatment and Evaluation Program (STEP), Veterans Affairs San Diego Healthcare System, San Diego, California, USA. * John R Kelsoe Consortia * Psychiatric GWAS Consortium Bipolar Disorder Working Group * Pamela Sklar, * Stephan Ripke, * Laura J Scott, * Ole A Andreassen, * Sven Cichon, * Nick Craddock, * Howard J Edenberg, * John I Nurnberger Jr, * Marcella Rietschel, * Douglas Blackwood, * Aiden Corvin, * Matthew Flickinger, * Weihua Guan, * Morten Mattingsdal, * Andrew McQuillin, * Phoenix Kwan, * Thomas F Wienker, * Mark Daly, * Frank Dudbridge, * Peter A Holmans, * Danyu Lin, * Margit Burmeister, * Tiffany A Greenwood, * Marian L Hamshere, * Pierandrea Muglia, * Erin N Smith, * Peter P Zandi, * Caroline M Nievergelt, * Rebecca McKinney, * Paul D Shilling, * Nicholas J Schork, * Cinnamon S Bloss, * Tatiana Foroud, * Daniel L Koller, * Elliot S Gershon, * Chunyu Liu, * Judith A Badner, * William A Scheftner, * William B Lawson, * Evaristus A Nwulia, * Maria Hipolito, * William Coryell, * John Rice, * William Byerley, * Francis J McMahon, * Thomas G Schulze, * Wade Berrettini, * Falk W Lohoff, * James B Potash, * Pamela B Mahon, * Melvin G McInnis, * Sebastian Zöllner, * Peng Zhang, * David W Craig, * Szabocls Szelinger, * Thomas B Barrett, * René Breuer, * Sandra Meier, * Jana Strohmaier, * Stephanie H Witt, * Federica Tozzi, * Anne Farmer, * Peter McGuffin, * John Strauss, * Wei Xu, * James L Kennedy, * John B Vincent, * Keith Matthews, * Richard Day, * Manuel A Ferreira, * Colm O'Dushlaine, * Roy Perlis, * Soumya Raychaudhuri, * Douglas Ruderfer, * Phil L Hyoun, * Jordan W Smoller, * Jun Li, * Devin Absher, * Robert C Thompson, * Fan Guo Meng, * Alan F Schatzberg, * William E Bunney, * Jack D Barchas, * Edward G Jones, * Stanley J Watson, * Richard M Myers, * Huda Akil, * Michael Boehnke, * Kim Chambert, * Jennifer Moran, * Ed Scolnick, * Srdjan Djurovic, * Ingrid Melle, * Gunnar Morken, * Michael Gill, * Derek Morris, * Emma Quinn, * Thomas W Mühleisen, * Franziska A Degenhardt, * Manuel Mattheisen, * Johannes Schumacher, * Wolfgang Maier, * Michael Steffens, * Peter Propping, * Markus M Nöthen, * Adebayo Anjorin, * Nick Bass, * Hugh Gurling, * Radhika Kandaswamy, * Jacob Lawrence, * Kevin McGhee, * Andrew McIntosh, * Alan W McLean, * Walter J Muir, * Benjamin S Pickard, * Gerome Breen, * David St. Clair, * Sian Caesar, * Katherine Gordon-Smith, * Lisa Jones, * Christine Fraser, * Elaine K Green, * Detelina Grozeva, * Ian R Jones, * George Kirov, * Valentina Moskvina, * Ivan Nikolov, * Michael C O'Donovan, * Michael J Owen, * David A Collier, * Amanda Elkin, * Richard Williamson, * Allan H Young, * I Nicol Ferrier, * Kari Stefansson, * Hreinn Stefansson, * Þorgeir Þorgeirsson, * Stacy Steinberg, * Ómar Gustafsson, * Sarah E Bergen, * Vishwajit Nimgaonkar, * Christina Hultman, * Mikael Landén, * Paul Lichtenstein, * Patrick Sullivan, * Martin Schalling, * Urban Osby, * Lena Backlund, * Louise Frisén, * Niklas Langstrom, * Stéphane Jamain, * Marion Leboyer, * Bruno Etain, * Frank Bellivier, * Hannes Petursson, * Engilbert Sigur∂sson, * Bertram Müller-Mysok, * Susanne Lucae, * Markus Schwarz, * Peter R Schofield, * Nick Martin, * Grant W Montgomery, * Mark Lathrop, * Högni Óskarsson, * Michael Bauer, * Adam Wright, * Philip B Mitchell, * Martin Hautzinger, * Andreas Reif, * John R Kelsoe & * Shaun M Purcell Contributions P. Sklar. (chair), O.A.A., S. Chichon, N.C., H.J.E., J.R.K., J.I.N., S.M.P., M.R., S. Ripke, L.J.S. S.M.P. (chair), D.B., A.C., N.C., M.A.F., M.F., W.G., J.R.K., M. Mattingsdal, A. McQuillin, P.K., S. Ripke, L.J.S., P. Sklar, T.F.W. : S. Ripke (chair), M.D., F.D., P.A.H., D.L. J.R.K. (co-chair), P. Sklar. (co-chair), O.A.A., D.B., M. Burmeister, S. Chichon, N.C., T.A.G., M.L.H., S.M.P., P. Muglia, J.I.N., L.J.S., E.N.S., P.P.Z. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Pamela Sklar Author Details Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (3276K) Supplementary Note, Supplementary Figures 1–6 and Supplementary Tables 1–10. Additional data
• Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci
  - Nat Genet 43(10):984-989 (2011)
  Nature Genetics | Letter Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci * Jaspal S Kooner1, 2, 3, 46 * Danish Saleheen4, 5, 46 * Xueling Sim6, 46 * Joban Sehmi1, 2, 46 * Weihua Zhang7, 46 * Philippe Frossard4, 46 * Latonya F Been8 * Kee-Seng Chia6, 9 * Antigone S Dimas10, 11 * Neelam Hassanali12 * Tazeen Jafar13, 14 * Jeremy B M Jowett15 * Xinzhong Li1 * Venkatesan Radha16 * Simon D Rees17, 18 * Fumihiko Takeuchi19 * Robin Young5 * Tin Aung20, 21 * Abdul Basit22 * Manickam Chidambaram16 * Debashish Das2 * Elin Grundberg23 * Åsa K Hedman11 * Zafar I Hydrie22 * Muhammed Islam13 * Chiea-Chuen Khor6, 21, 24 * Sudhir Kowlessur25 * Malene M Kristensen15 * Samuel Liju16 * Wei-Yen Lim6 * David R Matthews12 * Jianjun Liu24 * Andrew P Morris11 * Alexandra C Nica10 * Janani M Pinidiyapathirage26 * Inga Prokopenko11 * Asif Rasheed4 * Maria Samuel4 * Nabi Shah4 * A Samad Shera27 * Kerrin S Small23, 28 * Chen Suo6 * Ananda R Wickremasinghe26 * Tien Yin Wong20, 21, 29 * Mingyu Yang30 * Fan Zhang30 * DIAGRAM * MuTHER * Goncalo R Abecasis32 * Anthony H Barnett17, 18 * Mark Caulfield33 * Panos Deloukas34 * Timothy M Frayling35 * Philippe Froguel36 * Norihiro Kato19 * Prasad Katulanda12, 37 * M Ann Kelly17, 18 * Junbin Liang30 * Viswanathan Mohan16, 38 * Dharambir K Sanghera8 * James Scott1 * Mark Seielstad39 * Paul Z Zimmet15 * Paul Elliott7, 40, 46 * Yik Ying Teo6, 9, 24, 41, 42, 46 * Mark I McCarthy11, 12, 43, 46 * John Danesh5, 46 * E Shyong Tai9, 44, 45, 46 * John C Chambers2, 3, 7, 46 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:984–989Year published:(2011)DOI:doi:10.1038/ng.921Received04 January 2011Accepted03 August 2011Published online28 August 2011Corrected online16 September 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10−4 for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10−8 to P = 1.9 × 10−11). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10−4), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a ! population with increased susceptibility to T2D. View full text Figures at a glance * Figure 1: Summary of study design. * Figure 2: Manhattan plot for the primary South Asian genome-wide association analysis of men and women using directly genotyped SNPs. At the six new loci reaching genome wide-significance, the sentinel SNPs are indicated with a green dot for the GWAS result and a red dot for the combined analysis of the GWAS and replication data in South Asians. * Figure 3: Regional plots for the six loci associated with type 2 diabetes in South Asians. Shown are the GRB14 region (), ST6GAL1 region (), VPS26A region (), HMG20A region (), AP3S2 region () and HNF4A region (). For the sentinel SNP, a purple circle represents the genome-wide result, and a purple diamond represents the combined analysis with the replication studies. Other genotyped SNPs are color coded according to their pairwise LD with the sentinel SNP calculated in a representative sample of 83 South Asians from the Singapore Genome Variation Project36. The recombination rates estimated from the HapMap2 combined panels are shown. Regional plots also incorporating SNPs imputed from HapMap2 are shown in Supplementary Figures 7 and 8. Change history * Change history * Author information * Supplementary informationCorrected online 16 September 2011In the version of this article initially published online, Elin Grundberg's name was misspelled as Elin Grunberg, and Xinzhong Li's name was misspelled as Xinzhing Li. The error has been corrected for the print, PDF and HTML versions of the article. Author information * Change history * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Jaspal S Kooner, * Danish Saleheen, * Xueling Sim, * Joban Sehmi, * Weihua Zhang, * Philippe Frossard, * Paul Elliott, * Yik Ying Teo, * Mark I McCarthy, * John Danesh, * E Shyong Tai & * John C Chambers Affiliations * National Heart and Lung Institute (NHLI), Imperial College London, Hammersmith Hospital, London, UK. * Jaspal S Kooner, * Joban Sehmi, * Xinzhong Li & * James Scott * Ealing Hospital National Health Service (NHS) Trust, Middlesex, UK. * Jaspal S Kooner, * Joban Sehmi, * Debashish Das & * John C Chambers * Imperial College Healthcare NHS Trust, London, UK. * Jaspal S Kooner & * John C Chambers * Center for Non-Communicable Diseases Pakistan, Karachi, Pakistan. * Danish Saleheen, * Philippe Frossard, * Asif Rasheed, * Maria Samuel & * Nabi Shah * Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. * Danish Saleheen, * Robin Young & * John Danesh * Centre for Molecular Epidemiology, National University of Singapore, Singapore. * Xueling Sim, * Kee-Seng Chia, * Chiea-Chuen Khor, * Wei-Yen Lim, * Chen Suo & * Yik Ying Teo * Epidemiology and Biostatistics, Imperial College London, London, UK. * Weihua Zhang, * Paul Elliott & * John C Chambers * Department of Pediatrics, Section of Genetics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. * Latonya F Been & * Dharambir K Sanghera * Department of Epidemiology and Public Health, National University of Singapore, Singapore. * Kee-Seng Chia, * Yik Ying Teo & * E Shyong Tai * Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland. * Antigone S Dimas & * Alexandra C Nica * Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. * Antigone S Dimas, * Åsa K Hedman, * Andrew P Morris, * Inga Prokopenko & * Mark I McCarthy * Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Churchill Hospital, Oxford, UK. * Neelam Hassanali, * David R Matthews, * Prasad Katulanda & * Mark I McCarthy * Department of Community Health Sciences, Aga Khan University, Karachi, Pakistan. * Tazeen Jafar & * Muhammed Islam * Department of Medicine, Aga Khan University, Karachi, Pakistan. * Tazeen Jafar * Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia. * Jeremy B M Jowett, * Malene M Kristensen & * Paul Z Zimmet * Department of Molecular Genetics, Madras Diabetes Research Foundation–Indian Council of Medical Research (ICMR) Advanced Centre for Genomics of Diabetes, Chennai, India. * Venkatesan Radha, * Manickam Chidambaram, * Samuel Liju & * Viswanathan Mohan * College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. * Simon D Rees, * Anthony H Barnett & * M Ann Kelly * BioMedical Research Centre, Heart of England NHS Foundation Trust, Birmingham, UK. * Simon D Rees, * Anthony H Barnett & * M Ann Kelly * Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan. * Fumihiko Takeuchi & * Norihiro Kato * Department of Ophthalmology, National University of Singapore, Singapore. * Tin Aung & * Tien Yin Wong * Singapore Eye Research Institute, Singapore National Eye Centre, Singapore. * Tin Aung, * Chiea-Chuen Khor & * Tien Yin Wong * Baqai Institute of Diabetology and Endocrinology, Karachi, Pakistan. * Abdul Basit & * Zafar I Hydrie * Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. * Elin Grundberg & * Kerrin S Small * Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore. * Chiea-Chuen Khor, * Jianjun Liu & * Yik Ying Teo * Ministry of Health, Port Louis, Mauritius. * Sudhir Kowlessur * Department of Public Health, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka. * Janani M Pinidiyapathirage & * Ananda R Wickremasinghe * Diabetic Association Pakistan, Karachi, Pakistan. * A Samad Shera * Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. * Kerrin S Small * Center for Eye Research Australia, University of Melbourne, Melbourne, Victoria, Australia. * Tien Yin Wong * Beijing Genomics Institute, Shenzhen, China. * Mingyu Yang, * Fan Zhang & * Junbin Liang * Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA. * Goncalo R Abecasis * Clinical Pharmacology and Barts and the London Genome Centre, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK. * Mark Caulfield * Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. * Panos Deloukas * Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, Exeter, UK. * Timothy M Frayling * Genomics of Common Diseases, School of Public Health, Imperial College London, Hammersmith Hospital, London, UK. * Philippe Froguel * Diabetes Research Unit, Department of Clinical Medicine, University of Colombo, Colombo, Sri Lanka. * Prasad Katulanda * Dr Mohan's Diabetes Specialties Centre, Chennai, India. * Viswanathan Mohan * Institute of Human Genetics, University of California, San Francisco, California, USA. * Mark Seielstad * Medical Research Council (MRC)-Health Protection Agency (HPA) Centre for Environment and Health, Imperial College London, London, UK. * Paul Elliott * Department of Statistics and Applied Probability, National University of Singapore, Singapore. * Yik Ying Teo * National University of Singapore Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore. * Yik Ying Teo * Oxford National Institute for Health Research (NIHR) Biomedical Research Centre, Churchill Hospital, Oxford, UK. * Mark I McCarthy * Department of Medicine, National University of Singapore, Singapore. * E Shyong Tai * Duke-National University of Singapore Graduate Medical School, Singapore. * E Shyong Tai Consortia * DIAGRAM * MuTHER Contributions J.S.K., D.S., X.S., J. Sehmi, W.Z., P.E., Y.Y.T., M.I.M., J.D., E.S.T. and J.C.C. wrote the manuscript. All authors read and provided critical comment on the manuscript. COBRA study: T.J., M.I. and T.M.F. Chennai Urban Rural Epidemiology Study: V.R., M. Chidambaram, S.L. and V.M. Diabetes Genetics in Pakistan and UK Asian Diabetes Studies: S.D.R., A.B., Z.I.H., A.S.S., A.H.B. and M.A.K. London Life Sciences Population Study: J.S.K., W.Z., J. Sehmi, X.L., D.D., G.R.A., J. Scott, M. Caulfield, P. Froguel, P.E., M.I.M. and J.C.C. Mauritius study: J.B.M.J., S.K., M.M.K. and P.Z.Z. Pakistan Risk of Myocardial Infarction Study: D.S., P. Frossard, R.Y., A.R., M. Samuel, N.S., P.D. and J.D. Ragama Health Study: N.K., F.T., A.R.W. and J.M.P. Singapore Consortium of Cohort Studies: K.-S.C., W.-Y.L., C.-C.K., J. Liu and E.S.T. Sikh Diabetes Study: L.F.B. and D.K.S. Singapore Indian Eye Study: X.S., C.S., T.A., T.Y.W., M. Seielstad, Y.Y.T. and E.S.T. Sri Lankan Diabetes Study: N.H., I.! P., D.R.M., P.K. and M.I.M. M.Y., F.Z., J. Liang, X.L., J.S.K. and J.C.C. A.P.M. and M.I.M. A.S.D., E.G., Å.K.H., A.C.N., K.S.S. and M.I.M. A list of members is provided in the Supplementary Note. DIAGRAM MuTHER Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * John C Chambers or * Jaspal S Kooner Author Details * Jaspal S Kooner Contact Jaspal S Kooner Search for this author in: * NPG journals * PubMed * Google Scholar * Danish Saleheen Search for this author in: * NPG journals * PubMed * Google Scholar * Xueling Sim Search for this author in: * NPG journals * PubMed * Google Scholar * Joban Sehmi Search for this author in: * NPG journals * PubMed * Google Scholar * Weihua Zhang Search for this author in: * NPG journals * PubMed * Google Scholar * Philippe Frossard Search for this author in: * NPG journals * PubMed * Google Scholar * Latonya F Been Search for this author in: * NPG journals * PubMed * Google Scholar * Kee-Seng Chia Search for this author in: * NPG journals * PubMed * Google Scholar * Antigone S Dimas Search for this author in: * NPG journals * PubMed * Google Scholar * Neelam Hassanali Search for this author in: * NPG journals * PubMed * Google Scholar * Tazeen Jafar Search for this 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• Large-scale genome-wide association studies in east Asians identify new genetic loci influencing metabolic traits
  - Nat Genet 43(10):990-995 (2011)
  Nature Genetics | Letter Large-scale genome-wide association studies in east Asians identify new genetic loci influencing metabolic traits * Young Jin Kim1, 14 * Min Jin Go1, 14 * Cheng Hu2 * Chang Bum Hong1 * Yun Kyoung Kim1 * Ji Young Lee1 * Joo-Yeon Hwang1 * Ji Hee Oh1 * Dong-Joon Kim1 * Nam Hee Kim1 * Soeui Kim1 * Eun Jung Hong1 * Ji-Hyun Kim1 * Haesook Min1 * Yeonjung Kim1 * Rong Zhang2 * Weiping Jia2 * Yukinori Okada3, 4 * Atsushi Takahashi3 * Michiaki Kubo3 * Toshihiro Tanaka3 * Naoyuki Kamatani3 * Koichi Matsuda5 * MAGIC consortium * Taesung Park7 * Bermseok Oh8 * Kuchan Kimm9 * Daehee Kang10 * Chol Shin11 * Nam H Cho12 * Hyung-Lae Kim1, 13 * Bok-Ghee Han1 * Jong-Young Lee1 * Yoon Shin Cho1 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:990–995Year published:(2011)DOI:doi:10.1038/ng.939Received22 December 2010Accepted18 August 2011Published online11 September 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg To identify the genetic bases for nine metabolic traits, we conducted a meta-analysis combining Korean genome-wide association results from the KARE project (n = 8,842) and the HEXA shared control study (n = 3,703). We verified the associations of the loci selected from the discovery meta-analysis in the replication stage (30,395 individuals from the BioBank Japan genome-wide association study and individuals comprising the Health2 and Shanghai Jiao Tong University Diabetes cohorts). We identified ten genome-wide significant signals newly associated with traits from an overall meta-analysis. The most compelling associations involved 12q24.11 (near MYL2) and 12q24.13 (in C12orf51) for high-density lipoprotein cholesterol, 2p21 (near SIX2-SIX3) for fasting plasma glucose, 19q13.33 (in RPS11) and 6q22.33 (in RSPO3) for renal traits, and 12q24.11 (near MYL2), 12q24.13 (in C12orf51 and near OAS1), 4q31.22 (in ZNF827) and 7q11.23 (near TBL2-BCL7B) for hepatic traits. These finding! s highlight previously unknown biological pathways for metabolic traits investigated in this study. View full text Figures at a glance * Figure 1: Overall study scheme. * Figure 2: Regional plot of new variants that reached genome-wide significance (overall meta P < 5 × 10−8). (–) The new genome-wide significant loci. In the top panel of each, the association signals scaled by −log10P (typed or imputed SNPs) at each locus are distributed in a genomic region 400 kb to either side of the lead association signal (typed). Each SNP is plotted as a circle along the chromosomal position, and linkage disequilibrium between the lead SNP and the other SNPs is colored as a scale from low (blue) to high (red) or is colored gray if linkage disequilibrium information was not available in the HapMap phase 2 CHB+JPT samples. The lead SNP is colored purple, and the overall meta-analysis result is shown with a purple diamond. The recombination rate estimated from HapMap phase 2 is plotted in blue. The bottom panels illustrate the locations of known genes. Genetic information is based on NCBI build 36 and dbSNP build 129. HDLc, high density lipoprotein cholesterol; FPG, fasting plasma glucose; ALB, albumin; BUN, blood urea nitrogen; GGT, gamma glutamyl transfera! se; ALT, alanine aminotransferase; AST, aspartate aminotransferase. Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Young Jin Kim & * Min Jin Go Affiliations * Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex, Chungcheongbuk-do, Korea. * Young Jin Kim, * Min Jin Go, * Chang Bum Hong, * Yun Kyoung Kim, * Ji Young Lee, * Joo-Yeon Hwang, * Ji Hee Oh, * Dong-Joon Kim, * Nam Hee Kim, * Soeui Kim, * Eun Jung Hong, * Ji-Hyun Kim, * Haesook Min, * Yeonjung Kim, * Hyung-Lae Kim, * Bok-Ghee Han, * Jong-Young Lee & * Yoon Shin Cho * Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. * Cheng Hu, * Rong Zhang & * Weiping Jia * Center for Genomic Medicine, RIKEN, Kanagawa, Japan. * Yukinori Okada, * Atsushi Takahashi, * Michiaki Kubo, * Toshihiro Tanaka & * Naoyuki Kamatani * Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. * Yukinori Okada * Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan. * Koichi Matsuda * Department of Statistics, College of Natural Science, Seoul National University, Seoul, Korea. * Taesung Park * Department of Biomedical Engineering, School of Medicine, Kyung Hee University, Seoul, Korea. * Bermseok Oh * Merck Research Laboratories, External Scientific Affairs, Merck, Sharp & Dohme Korea, Seoul, Korea. * Kuchan Kimm * Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea. * Daehee Kang * Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Korea. * Chol Shin * Department of Preventive Medicine, Ajou University School of Medicine, Suwon, Korea. * Nam H Cho * Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, Korea. * Hyung-Lae Kim Consortia * MAGIC consortium Contributions The study was supervised by J.-Y.L., Y.S.C., T.T., N.K., K.M., W.J., K.K., B.O., H.-L.K. and B.-G.H. Genotyping experiments were designed by Y.S.C., B.O., M.K., C.H., H.-L.K. and J.-Y.L. Genotyping experiments were performed by J.H.O., D.-J.K., M.K., C.H. and R.Z. DNA sample preparation was carried out by E.J.H. and J.-H.K. Phenotype information was collected by N.H.K., S.K., H.M., Y.K., N.H.C., C.S. and D.K. Statistical analysis was performed by M.J.G., Y.K., Y.K.K., J.Y.L., S.K., Y.O., A.T., C.H. and T.P. Bioinformatic analysis was conducted by Y.J.K., C.B.H., M.J.G., C.H., J.-Y.H. and Y.S.C. The manuscript was written by Y.J.K., M.J.G., Y.O. and Y.S.C. All authors reviewed the manuscript. A full list of members is provided in the Supplementary Note. MAGIC consortium Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Yoon Shin Cho Author Details * Young Jin Kim Search for this author in: * NPG journals * PubMed * Google Scholar * Min Jin Go Search for this author in: * NPG journals * PubMed * Google Scholar * Cheng Hu Search for this author in: * NPG journals * PubMed * Google Scholar * Chang Bum Hong Search for this author in: * NPG journals * PubMed * Google Scholar * Yun Kyoung Kim Search for this author in: * NPG journals * PubMed * Google Scholar * Ji Young Lee Search for this author in: * NPG journals * PubMed * Google Scholar * Joo-Yeon Hwang Search for this author in: * NPG journals * PubMed * Google Scholar * Ji Hee Oh Search for this author in: * NPG journals * PubMed * Google Scholar * Dong-Joon Kim Search for this author in: * NPG journals * PubMed * Google Scholar * Nam Hee Kim Search for this author in: * NPG journals * PubMed * Google Scholar * Soeui Kim Search for this author in: * NPG journals * PubMed * Google Scholar * Eun Jung Hong Search for this author in: * NPG journals * PubMed * Google Scholar * Ji-Hyun Kim Search for this author in: * NPG journals * PubMed * Google Scholar * Haesook Min Search for this author in: * NPG journals * PubMed * Google Scholar * Yeonjung Kim Search for this author in: * NPG journals * PubMed * Google Scholar * Rong Zhang Search for this author in: * NPG journals * PubMed * Google Scholar * Weiping Jia Search for this author in: * NPG journals * PubMed * Google Scholar * Yukinori Okada Search for this author in: * NPG journals * PubMed * Google Scholar * Atsushi Takahashi Search for this author in: * NPG journals * PubMed * Google Scholar * Michiaki Kubo Search for this author in: * NPG journals * PubMed * Google Scholar * Toshihiro Tanaka Search for this author in: * NPG journals * PubMed * Google Scholar * Naoyuki Kamatani Search for this author in: * NPG journals * PubMed * Google Scholar * Koichi Matsuda Search for this author in: * NPG journals * PubMed * Google Scholar * MAGIC consortium * Taesung Park Search for this author in: * NPG journals * PubMed * Google Scholar * Bermseok Oh Search for this author in: * NPG journals * PubMed * Google Scholar * Kuchan Kimm Search for this author in: * NPG journals * PubMed * Google Scholar * Daehee Kang Search for this author in: * NPG journals * PubMed * Google Scholar * Chol Shin Search for this author in: * NPG journals * PubMed * Google Scholar * Nam H Cho Search for this author in: * NPG journals * PubMed * Google Scholar * Hyung-Lae Kim Search for this author in: * NPG journals * PubMed * Google Scholar * Bok-Ghee Han Search for this author in: * NPG journals * PubMed * Google Scholar * Jong-Young Lee Search for this author in: * NPG journals * PubMed * Google Scholar * Yoon Shin Cho Contact Yoon Shin Cho Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (6M) Supplementary Note, Supplementary Tables 1–9 and Supplementary Figures 1–5. 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• Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1
  - Nat Genet 43(10):996-1000 (2011)
  Nature Genetics | Letter Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1 * Scott A LeMaire1, 2, 17 * Merry-Lynn N McDonald3, 17 * Dong-chuan Guo4, 17 * Ludivine Russell1, 2 * Charles C Miller III5 * Ralph J Johnson4 * Mir Reza Bekheirnia3 * Luis M Franco3 * Mary Nguyen1, 2 * Reed E Pyeritz6 * Joseph E Bavaria7 * Richard Devereux8 * Cheryl Maslen9 * Kathryn W Holmes10 * Kim Eagle11 * Simon C Body12 * Christine Seidman13 * J G Seidman13 * Eric M Isselbacher14 * Molly Bray15 * Joseph S Coselli1, 2 * Anthony L Estrera5 * Hazim J Safi5 * John W Belmont3 * Suzanne M Leal3 * Dianna M Milewicz4, 16 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:996–1000Year published:(2011)DOI:doi:10.1038/ng.934Received23 May 2011Accepted09 August 2011Published online11 September 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Although thoracic aortic aneurysms and dissections (TAAD) can be inherited as a single-gene disorder, the genetic predisposition in the majority of affected people is poorly understood. In a multistage genome-wide association study (GWAS), we compared 765 individuals who had sporadic TAAD (STAAD) with 874 controls and identified common SNPs at a 15q21.1 locus that were associated with STAAD, with odds ratios of 1.6–1.8 that achieved genome-wide significance. We followed up 107 SNPs associated with STAAD with P < 1 × 10−5 in the region, in two separate STAAD cohorts. The associated SNPs fall into a large region of linkage disequilibrium encompassing FBN1, which encodes fibrillin-1. FBN1 mutations cause Marfan syndrome, whose major cardiovascular complication is TAAD. This study shows that common genetic variants at 15q21.1 that probably act via FBN1 are associated with STAAD, suggesting a common pathogenesis of aortic disease in Marfan syndrome and STAAD. View full text Figures at a glance * Figure 1: A Manhattan plot of stage 1 genome-wide association results from comparison of STAAD cases to NINDS controls. For each tested marker, the significance is displayed on the y-axis as the −log10 of the P value. The −log10 results are ordered along the x-axis by chromosome, with each colored bar representing a different chromosome. * Figure 2: FBN1 regional association plots. (–) Association plots are shown for STAAD (), STAAD with BAV () and aortic dissection (). The top-ranked stage 1 SNP for each phenotype is marked by a blue diamond. Red, pink and yellow shading denotes r2 (see key), corresponding to the linkage disequilibrium between the top-ranked SNP and other SNPs in the region. The recombination rate according to HapMap CEU is plotted as a light blue line, with amplitude scaled to the right-hand y-axis. Circles denote the five SNPs genotyped in the FBN1 region that were associated with TAAD in stage 1 with GWS. Dotted lines denote –log10P = 0. Green triangles denote the fixed-effects meta-analysis results for the combined stages. When the result of the Cochran Q test of homogeneity was <0.1, random-effects meta-analysis results are shown; otherwise fixed-effects meta-analysis was performed. Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Scott A LeMaire, * Merry-Lynn N McDonald & * Dong-chuan Guo Affiliations * Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA. * Scott A LeMaire, * Ludivine Russell, * Mary Nguyen & * Joseph S Coselli * Cardiovascular Surgery, Texas Heart Institute, St. Luke's Episcopal Hospital, Houston, Texas, USA. * Scott A LeMaire, * Ludivine Russell, * Mary Nguyen & * Joseph S Coselli * Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. * Merry-Lynn N McDonald, * Mir Reza Bekheirnia, * Luis M Franco, * John W Belmont & * Suzanne M Leal * Division of Medical Genetics, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA. * Dong-chuan Guo, * Ralph J Johnson & * Dianna M Milewicz * Department of Cardiothoracic and Vascular Surgery, University of Texas Health Science Center at Houston, Houston, Texas, USA. * Charles C Miller III, * Anthony L Estrera & * Hazim J Safi * Division of Medical Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. * Reed E Pyeritz * Division of Cardiovascular Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. * Joseph E Bavaria * Greenberg Division of Cardiology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. * Richard Devereux * Division of Cardiovascular Medicine, Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, Oregon, USA. * Cheryl Maslen * Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. * Kathryn W Holmes * Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA. * Kim Eagle * Department of Anesthesiology, Harvard Medical School, Boston, Massachusetts, USA. * Simon C Body * Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. * Christine Seidman & * J G Seidman * Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. * Eric M Isselbacher * Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. * Molly Bray * Medicine Services, Texas Heart Institute, St. Luke's Episcopal Hospital, Houston, Texas, USA. * Dianna M Milewicz Contributions S.A.L., J.W.B. and D.M.M. were the principal investigators who conducted the study. S.A.L. and D.M.M. coordinated and oversaw the study. L.R., R.J.J., C.C.M., D.M.M., S.A.L., J.S.C., H.J.S. and A.L.E. participated in study enrollment for stages 1 and 2, helped gather related detailed clinical information and biological samples, and helped carry out the clinical analysis. R.E.P., J.E.B., R.D., C.M., K.W.H., K.E., S.C.B., C.S., J.G.S. and E.M.I. participated in study enrollment for stages 2 and 3 and helped gather related detailed clinical information and biological samples. D.G. and M.N. participated in the preparation of biological samples. M.B., J.W.B., M.R.B. and L.M.F. carried out the genotyping. M.-L.N.M. and S.M.L. were responsible for bioinformatics and all statistical analyses. S.A.L., M.-L.N.M., D.G., S.M.L. and D.M.M. wrote the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Dianna M Milewicz Author Details * Scott A LeMaire Search for this author in: * NPG journals * PubMed * Google Scholar * Merry-Lynn N McDonald Search for this author in: * NPG journals * PubMed * Google Scholar * Dong-chuan Guo Search for this author in: * NPG journals * PubMed * Google Scholar * Ludivine Russell Search for this author in: * NPG journals * PubMed * Google Scholar * Charles C Miller III Search for this author in: * NPG journals * PubMed * Google Scholar * Ralph J Johnson Search for this author in: * NPG journals * PubMed * Google Scholar * Mir Reza Bekheirnia Search for this author in: * NPG journals * PubMed * Google Scholar * Luis M Franco Search for this author in: * NPG journals * PubMed * Google Scholar * Mary Nguyen Search for this author in: * NPG journals * PubMed * Google Scholar * Reed E Pyeritz Search for this author in: * NPG journals * PubMed * Google Scholar * Joseph E Bavaria Search for this author in: * NPG journals * PubMed * Google Scholar * Richard Devereux Search for this author in: * NPG journals * PubMed * Google Scholar * Cheryl Maslen Search for this author in: * NPG journals * PubMed * Google Scholar * Kathryn W Holmes Search for this author in: * NPG journals * PubMed * Google Scholar * Kim Eagle Search for this author in: * NPG journals * PubMed * Google Scholar * Simon C Body Search for this author in: * NPG journals * PubMed * Google Scholar * Christine Seidman Search for this author in: * NPG journals * PubMed * Google Scholar * J G Seidman Search for this author in: * NPG journals * PubMed * Google Scholar * Eric M Isselbacher Search for this author in: * NPG journals * PubMed * Google Scholar * Molly Bray Search for this author in: * NPG journals * PubMed * Google Scholar * Joseph S Coselli Search for this author in: * NPG journals * PubMed * Google Scholar * Anthony L Estrera Search for this author in: * NPG journals * PubMed * Google Scholar * Hazim J Safi Search for this author in: * NPG journals * PubMed * Google Scholar * John W Belmont Search for this author in: * NPG journals * PubMed * Google Scholar * Suzanne M Leal Search for this author in: * NPG journals * PubMed * Google Scholar * Dianna M Milewicz Contact Dianna M Milewicz Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (1M) Supplementary Figures 1 and 2; Supplementary Tables 1-11 Additional data
• Genome-wide association study identifies two susceptibility loci for exudative age-related macular degeneration in the Japanese population
  - Nat Genet 43(10):1001-1004 (2011)
  Nature Genetics | Letter Genome-wide association study identifies two susceptibility loci for exudative age-related macular degeneration in the Japanese population * Satoshi Arakawa1, 2 * Atsushi Takahashi3 * Kyota Ashikawa1 * Naoya Hosono1 * Tomomi Aoi1 * Miho Yasuda2 * Yuji Oshima2 * Shigeo Yoshida2 * Hiroshi Enaida2 * Takashi Tsuchihashi4 * Keisuke Mori4 * Shigeru Honda5 * Akira Negi5 * Akira Arakawa6 * Kazuaki Kadonosono6 * Yutaka Kiyohara7 * Naoyuki Kamatani3 * Yusuke Nakamura8 * Tatsuro Ishibashi2 * Michiaki Kubo1 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:1001–1004Year published:(2011)DOI:doi:10.1038/ng.938Received16 March 2011Accepted17 August 2011Published online11 September 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Age-related macular degeneration (AMD), the leading cause of irreversible blindness in the world, is a complex disease caused by multiple environmental and genetic risk factors. To identify genetic factors that modify the risk of exudative AMD in the Japanese population, we conducted a genome-wide association study and a replication study using a total of 1,536 individuals with exudative AMD and 18,894 controls. In addition to CFH (rs800292, P = 4.23 × 10−15) and ARMS2 (rs3750847, P = 8.67 × 10−29) loci, we identified two new susceptibility loci for exudative AMD: TNFRSF10A-LOC389641 on chromosome 8p21 (rs13278062, combined P = 1.03 × 10−12, odds ratio = 0.73) and REST-C4orf14-POLR2B-IGFBP7 on chromosome 4q12 (rs1713985, combined P = 2.34 × 10−8, odds ratio = 1.30). Fine mapping revealed that rs13278062, which is known to alter TNFRSF10A transcriptional activity, had the most significant association in 8p21 region. Our results provide new insights into the pathop! hysiology of exudative AMD. View full text Accession codes * Accession codes * Author information * Supplementary information Referenced accessions Gene Expression Omnibus * GSE18811 * GSE22317 Author information * Accession codes * Author information * Supplementary information Affiliations * Laboratory for Genotyping Development, Center for Genomic Medicine, RIKEN Yokohama Institute, Yokohama, Japan. * Satoshi Arakawa, * Kyota Ashikawa, * Naoya Hosono, * Tomomi Aoi & * Michiaki Kubo * Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. * Satoshi Arakawa, * Miho Yasuda, * Yuji Oshima, * Shigeo Yoshida, * Hiroshi Enaida & * Tatsuro Ishibashi * Laboratory for Statistical Analysis, Center for Genomic Medicine, RIKEN Yokohama Institute, Yokohama, Japan. * Atsushi Takahashi & * Naoyuki Kamatani * Department of Ophthalmology, Saitama Medical University, Saitama, Japan. * Takashi Tsuchihashi & * Keisuke Mori * Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Kobe, Japan. * Shigeru Honda & * Akira Negi * Department of Ophthalmology, Yokohama City University Medical Center, Yokohama, Japan. * Akira Arakawa & * Kazuaki Kadonosono * Department of Environmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. * Yutaka Kiyohara * Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan. * Yusuke Nakamura Contributions S.A., T.I., Y.N. and M.K. designed the study. S.A., N.H., K.A., T.A. and M.K. performed genotyping. S.A. and M.K. wrote the manuscript. A.T. performed statistical analysis at the genome-wide phase. Y.N. and M.K. managed DNA samples belonging to BioBank Japan. T.I. and Y.N. obtained funding for the study. M.Y., Y.O., S.Y. and H.E. collected GWAS samples. T.T., K.M., S.H., A.N., A.A. and K.K. collected case samples for the replication study. Y.K., N.K., Y.N. and M.K. supervised the study. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Michiaki Kubo Author Details * Satoshi Arakawa Search for this author in: * NPG journals * PubMed * Google Scholar * Atsushi Takahashi Search for this author in: * NPG journals * PubMed * Google Scholar * Kyota Ashikawa Search for this author in: * NPG journals * PubMed * Google Scholar * Naoya Hosono Search for this author in: * NPG journals * PubMed * Google Scholar * Tomomi Aoi Search for this author in: * NPG journals * PubMed * Google Scholar * Miho Yasuda Search for this author in: * NPG journals * PubMed * Google Scholar * Yuji Oshima Search for this author in: * NPG journals * PubMed * Google Scholar * Shigeo Yoshida Search for this author in: * NPG journals * PubMed * Google Scholar * Hiroshi Enaida Search for this author in: * NPG journals * PubMed * Google Scholar * Takashi Tsuchihashi Search for this author in: * NPG journals * PubMed * Google Scholar * Keisuke Mori Search for this author in: * NPG journals * PubMed * Google Scholar * Shigeru Honda Search for this author in: * NPG journals * PubMed * Google Scholar * Akira Negi Search for this author in: * NPG journals * PubMed * Google Scholar * Akira Arakawa Search for this author in: * NPG journals * PubMed * Google Scholar * Kazuaki Kadonosono Search for this author in: * NPG journals * PubMed * Google Scholar * Yutaka Kiyohara Search for this author in: * NPG journals * PubMed * Google Scholar * Naoyuki Kamatani Search for this author in: * NPG journals * PubMed * Google Scholar * Yusuke Nakamura Search for this author in: * NPG journals * PubMed * Google Scholar * Tatsuro Ishibashi Search for this author in: * NPG journals * PubMed * Google Scholar * Michiaki Kubo Contact Michiaki Kubo 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 1–3 and Supplementary Tables 1–7. 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• Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure
  - Nat Genet 43(10):1005-1011 (2011)
  Nature Genetics | Letter Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure * Louise V Wain1, 2, 179 * Germaine C Verwoert3, 4, 179 * Paul F O'Reilly5, 179 * Gang Shi6, 7, 179 * Toby Johnson8, 179 * Andrew D Johnson9, 10 * Murielle Bochud11, 12 * Kenneth M Rice13 * Peter Henneman14 * Albert V Smith15, 16 * Georg B Ehret17, 18, 19 * Najaf Amin20 * Martin G Larson9, 21 * Vincent Mooser22 * David Hadley23, 24 * Marcus Dörr25 * Joshua C Bis26 * Thor Aspelund15, 16 * Tõnu Esko27, 28, 29 * A Cecile J W Janssens20 * Jing Hua Zhao30 * Simon Heath31 * Maris Laan29 * Jingyuan Fu32, 33 * Giorgio Pistis34 * Jian'an Luan30 * Pankaj Arora35 * Gavin Lucas36 * Nicola Pirastu37 * Irene Pichler38 * Anne U Jackson39 * Rebecca J Webster40 * Feng Zhang41 * John F Peden42, 43 * Helena Schmidt44 * Toshiko Tanaka45 * Harry Campbell46 * Wilmar Igl47 * Yuri Milaneschi45 * Jouke-Jan Hottenga48 * Veronique Vitart49 * Daniel I Chasman50, 51 * Stella Trompet52, 53 * Jennifer L Bragg-Gresham39 * Behrooz Z Alizadeh32 * John C Chambers5, 54 * Xiuqing Guo55 * Terho Lehtimäki56 * Brigitte Kühnel57 * Lorna M Lopez58, 59 * Ozren Polašek60 * Mladen Boban61 * Christopher P Nelson62 * Alanna C Morrison63 * Vasyl Pihur17 * Santhi K Ganesh64 * Albert Hofman20 * Suman Kundu20 * Francesco U S Mattace-Raso3, 20 * Fernando Rivadeneira3, 4 * Eric J G Sijbrands3, 20 * Andre G Uitterlinden3, 4 * Shih-Jen Hwang9, 10, 65 * Ramachandran S Vasan9, 66 * Thomas J Wang9, 67 * Sven Bergmann68, 69 * Peter Vollenweider70 * Gérard Waeber70 * Jaana Laitinen71 * Anneli Pouta72, 73 * Paavo Zitting74 * Wendy L McArdle75 * Heyo K Kroemer76 * Uwe Völker77 * Henry Völzke78 * Nicole L Glazer79 * Kent D Taylor55 * Tamara B Harris80 * Helene Alavere27 * Toomas Haller27 * Aime Keis27 * Mari-Liis Tammesoo27 * Yurii Aulchenko20 * Inês Barroso81, 82 * Kay-Tee Khaw83 * Pilar Galan84, 85, 86 * Serge Hercberg84, 85, 86 * Mark Lathrop31 * Susana Eyheramendy87 * Elin Org29 * Siim Sõber29 * Xiaowen Lu32 * Ilja M Nolte32 * Brenda W Penninx88, 89, 90 * Tanguy Corre34 * Corrado Masciullo34 * Cinzia Sala34 * Leif Groop91 * Benjamin F Voight92 * Olle Melander93 * Christopher J O'Donnell94 * Veikko Salomaa95 * Adamo Pio d'Adamo37 * Antonella Fabretto96 * Flavio Faletra96 * Sheila Ulivi96 * Fabiola Del Greco M38 * Maurizio Facheris38 * Francis S Collins97 * Richard N Bergman98 * John P Beilby99, 100, 101 * Joseph Hung102, 101 * A William Musk101, 103, 104 * Massimo Mangino41 * So-Youn Shin41, 81 * Nicole Soranzo41, 81 * Hugh Watkins42, 43 * Anuj Goel42, 43 * Anders Hamsten105 * Pierre Gider44 * Marisa Loitfelder106 * Marion Zeginigg44 * Dena Hernandez107 * Samer S Najjar108, 109 * Pau Navarro49 * Sarah H Wild46 * Anna Maria Corsi110 * Andrew Singleton107 * Eco J C de Geus111 * Gonneke Willemsen111 * Alex N Parker112 * Lynda M Rose50 * Brendan Buckley113 * David Stott114 * Marco Orru115 * Manuela Uda115 * LifeLines Cohort Study * Melanie M van der Klauw116 * Weihua Zhang5, 54 * Xinzhong Li5 * James Scott117 * Yii-Der Ida Chen55 * Gregory L Burke118 * Mika Kähönen119 * Jorma Viikari120 * Angela Döring121, 122 * Thomas Meitinger123, 124 * Gail Davies59 * John M Starr58, 125 * Valur Emilsson15 * Andrew Plump126 * Jan H Lindeman127 * Peter A C 't Hoen14, 128 * Inke R König129 * EchoGen consortium * Janine F Felix4, 20, 130 * Robert Clarke131 * Jemma C Hopewell131 * Halit Ongen42 * Monique Breteler20 * Stéphanie Debette132 * Anita L DeStefano133 * Myriam Fornage134 * AortaGen Consortium * Gary F Mitchell135 * CHARGE Consortium Heart Failure Working Group * Nicholas L Smith136, 137, 138 * KidneyGen consortium * Hilma Holm139 * Kari Stefansson139, 140 * Gudmar Thorleifsson139 * Unnur Thorsteinsdottir139, 140 * CKDGen consortium * Cardiogenics consortium * CardioGram * Nilesh J Samani62, 141 * Michael Preuss142, 129 * Igor Rudan46, 143 * Caroline Hayward49 * Ian J Deary58, 59 * H-Erich Wichmann121, 144 * Olli T Raitakari145 * Walter Palmas146 * Jaspal S Kooner54, 117 * Ronald P Stolk147 * J Wouter Jukema52, 148, 149 * Alan F Wright49 * Dorret I Boomsma111 * Stefania Bandinelli150 * Ulf B Gyllensten47 * James F Wilson46 * Luigi Ferrucci45 * Reinhold Schmidt106 * Martin Farrall42, 43 * Tim D Spector41 * Lyle J Palmer40, 101, 151, 152 * Jaakko Tuomilehto153, 154, 155 * Arne Pfeufer38, 156, 157 * Paolo Gasparini37, 96 * David Siscovick26, 136, 158 * David Altshuler92, 159, 160, 161 * Ruth J F Loos30 * Daniela Toniolo34, 162 * Harold Snieder32 * Christian Gieger57 * Pierre Meneton163 * Nicholas J Wareham30 * Ben A Oostra164 * Andres Metspalu27, 28, 29 * Lenore Launer165 * Rainer Rettig166 * David P Strachan23 * Jacques S Beckmann68, 167 * Jacqueline C M Witteman4, 20 * Jeanette Erdmann142 * Ko Willems van Dijk14, 168 * Eric Boerwinkle169 * Michael Boehnke39 * Paul M Ridker50, 51, 170 * Marjo-Riitta Jarvelin5, 171, 172 * Aravinda Chakravarti17 * Goncalo R Abecasis39 * Vilmundur Gudnason15, 16 * Christopher Newton-Cheh35, 92 * Daniel Levy9, 10, 65 * Patricia B Munroe8, 179 * Bruce M Psaty26, 136, 173, 138, 179 * Mark J Caulfield8, 179 * Dabeeru C Rao6, 7, 174, 175, 179 * Martin D Tobin1, 2, 179 * Paul Elliott5, 176, 179 * Cornelia M van Duijn4, 20, 177, 179 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:1005–1011Year published:(2011)DOI:doi:10.1038/ng.922Received10 February 2011Accepted04 August 2011Published online11 September 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans1, 2, 3. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10−8 to P = 2.3 × 10−13) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differen! tially influence SBP and DBP. View full text Figures at a glance * Figure 1: Regional association plots of the eight SNPs at seven loci showing genome-wide significant association (P < 5 × 10−8) with pulse pressure (PP) and/or mean arterial pressure (MAP). (–) Shown is the statistical significance of each SNP on the –log10 scale as a function of chromosome position (NCBI build 36) in the meta-analysis of stage 1 only. The sentinel SNP at each locus is shown in blue; the correlations (r2) of each of the surrounding SNPs to the sentinel SNP are shown in the colors indicated in the key. The fine-scale recombination rate is shown in blue. Gene positions are indicated at the bottom. * Figure 2: Systolic blood pressure (SBP) and diastolic blood pressure (DBP) effect sizes (β coefficients) for all blood pressure SNPs identified in the present study and a concurrent study1 obtained from follow-up samples only. β coefficients are shown as standard deviation (s.d.) differences so that SBP and DBP are measured on comparable scales. Points are color coded according to whether they are genome-wide significant (P < 5 × 10−8) for pulse pressure (PP) (red), mean arterial pressure (MAP) (blue) or both MAP and PP (purple) in stages 1 and 2 of the present study, whereas those that are significant only for SBP and/or DBP from the concurrent study1 are shown in black. The new SNPs found in the present study are labeled with their rs numbers. For illustration purposes, the effect allele for each SNP is defined such that the direction of the SBP effect is always positive. Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Louise V Wain, * Germaine C Verwoert, * Paul F O'Reilly, * Gang Shi, * Toby Johnson, * Patricia B Munroe, * Bruce M Psaty, * Mark J Caulfield, * Dabeeru C Rao, * Martin D Tobin, * Paul Elliott & * Cornelia M van Duijn Affiliations * Department of Health Sciences, University of Leicester, Leicester, UK. * Louise V Wain & * Martin D Tobin * Department of Genetics, University of Leicester, Leicester, UK. * Louise V Wain & * Martin D Tobin * Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. * Germaine C Verwoert, * Francesco U S Mattace-Raso, * Fernando Rivadeneira, * Eric J G Sijbrands & * Andre G Uitterlinden * Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), The Netherlands. * Germaine C Verwoert, * Fernando Rivadeneira, * Andre G Uitterlinden, * Janine F Felix, * Jacqueline C M Witteman & * Cornelia M van Duijn * Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. * Paul F O'Reilly, * John C Chambers, * Weihua Zhang, * Xinzhong Li, * Marjo-Riitta Jarvelin & * Paul Elliott * Division of Biostatistics, Washington University in St. Louis, School of Medicine, Saint Louis, Missouri, USA. * Gang Shi & * Dabeeru C Rao * Department of Genetics, Washington University in St. Louis, School of Medicine, Saint Louis, Missouri, USA. * Gang Shi & * Dabeeru C Rao * 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, * Patricia B Munroe & * Mark J Caulfield * Framingham Heart Study, Framingham, Massachusetts, USA. * Andrew D Johnson, * Martin G Larson, * Shih-Jen Hwang, * Ramachandran S Vasan, * Thomas J Wang & * Daniel Levy * National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA. * Andrew D Johnson, * Shih-Jen Hwang & * Daniel Levy * Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. * Murielle Bochud * University of Lausanne, Lausanne, Switzerland. * Murielle Bochud * Department of Biostatistics, University of Washington, Seattle, Washington, USA. * Kenneth M Rice * Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. * Peter Henneman, * Peter A C 't Hoen & * Ko Willems van Dijk * Icelandic Heart Association, Kopavogur, Iceland. * Albert V Smith, * Thor Aspelund, * Valur Emilsson & * Vilmundur Gudnason * University of Iceland, Reykajvik, Iceland. * Albert V Smith, * Thor Aspelund & * Vilmundur Gudnason * Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. * Georg B Ehret, * Vasyl Pihur & * Aravinda Chakravarti * Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland. * Georg B Ehret * Cardiology, Department of Specialties of Internal Medicine, Geneva University Hospital, Geneva, Switzerland. * Georg B Ehret * Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands. * Najaf Amin, * A Cecile J W Janssens, * Albert Hofman, * Suman Kundu, * Francesco U S Mattace-Raso, * Eric J G Sijbrands, * Yurii Aulchenko, * Janine F Felix, * Monique Breteler, * Jacqueline C M Witteman & * Cornelia M van Duijn * Department of Mathematics, Boston University, Boston, Massachusetts, USA. * Martin G Larson * Genetics Division R&D, GlaxoSmithKline, King of Prussia, Pennsylvania, USA. * Vincent Mooser * Division of Community Health Sciences, St George's, University of London, London, UK. * David Hadley & * David P Strachan * Pediatric Epidemiology Center, University of South Florida, Tampa, Florida, USA. * David Hadley * Department of Internal Medicine B, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany. * Marcus Dörr * Cardiovascular Health Research Unit, Division of Internal Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA. * Joshua C Bis, * David Siscovick & * Bruce M Psaty * Estonian Genome Center, University of Tartu, Tartu, Estonia. * Tõnu Esko, * Helene Alavere, * Toomas Haller, * Aime Keis, * Mari-Liis Tammesoo & * Andres Metspalu * Estonian Biocenter, Tartu, Estonia. * Tõnu Esko & * Andres Metspalu * Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. * Tõnu Esko, * Maris Laan, * Elin Org, * Siim Sõber & * Andres Metspalu * Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Cambridge, UK. * Jing Hua Zhao, * Jian'an Luan, * Ruth J F Loos & * Nicholas J Wareham * Centre National de Génotypage, Commissariat à L'Energie Atomique, Institut de Génomique, Evry, France. * Simon Heath & * Mark Lathrop * Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. * Jingyuan Fu, * Behrooz Z Alizadeh, * Xiaowen Lu, * Ilja M Nolte & * Harold Snieder * Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. * Jingyuan Fu * Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy. * Giorgio Pistis, * Tanguy Corre, * Corrado Masciullo, * Cinzia Sala & * Daniela Toniolo * Center for Human Genetic Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. * Pankaj Arora & * Christopher Newton-Cheh * Cardiovascular Epidemiology and Genetics, Institut Municipal d'Investigacio Medica, Barcelona Biomedical Research Park, Barcelona, Spain. * Gavin Lucas * Institute for Maternal and Child Health–Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) 'Burlo Garofolo'—Trieste, University of Trieste, Trieste, Italy. * Nicola Pirastu, * Adamo Pio d'Adamo & * Paolo Gasparini * Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy. Affiliated Institute of the University of Lübeck, Lübeck, Germany. * Irene Pichler, * Fabiola Del Greco M, * Maurizio Facheris & * Arne Pfeufer * Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA. * Anne U Jackson, * Jennifer L Bragg-Gresham, * Michael Boehnke & * Goncalo R Abecasis * Centre for Genetic Epidemiology and Biostatistics, University of Western Australia, Crawley, Western Australia, Australia. * Rebecca J Webster & * Lyle J Palmer * Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. * Feng Zhang, * Massimo Mangino, * So-Youn Shin, * Nicole Soranzo & * Tim D Spector * Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. * John F Peden, * Hugh Watkins, * Anuj Goel, * Halit Ongen & * Martin Farrall * Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK. * John F Peden, * Hugh Watkins, * Anuj Goel & * Martin Farrall * Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria. * Helena Schmidt, * Pierre Gider & * Marion Zeginigg * Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, USA. * Toshiko Tanaka, * Yuri Milaneschi & * Luigi Ferrucci * Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK. * Harry Campbell, * Sarah H Wild, * Igor Rudan & * James F Wilson * Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden. * Wilmar Igl & * Ulf B Gyllensten * Neuroscience Campus Amsterdam (NCA), Department of Biological Psychology, VU University, Amsterdam, The Netherlands. * Jouke-Jan Hottenga * MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK. * Veronique Vitart, * Pau Navarro, * Caroline Hayward & * Alan F Wright * Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. * Daniel I Chasman, * Lynda M Rose & * Paul M Ridker * Harvard Medical School, Boston, Massachusetts, USA. * Daniel I Chasman & * Paul M Ridker * Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands. * Stella Trompet & * J Wouter Jukema * Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands. * Stella Trompet * Ealing Hospital National Health Service (NHS) Trust, Middlesex, UK. * John C Chambers, * Weihua Zhang & * Jaspal S Kooner * Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. * Xiuqing Guo, * Kent D Taylor & * Yii-Der Ida Chen * Department of Clinical Chemistry, University of Tampere and Tampere University Hospital, Tampere, Finland. * Terho Lehtimäki * Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. * Brigitte Kühnel & * Christian Gieger * Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK. * Lorna M Lopez, * John M Starr & * Ian J Deary * Department of Psychology, The University of Edinburgh, Edinburgh, UK. * Lorna M Lopez, * Gail Davies & * Ian J Deary * Department of Public Health, Medical School, University of Split, Split, Croatia. * Ozren Polašek * Department of Pharmacology, Medical School, University of Split, Split, Croatia. * Mladen Boban * Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK. * Christopher P Nelson & * Nilesh J Samani * Division of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, University of Texas at Houston Health Science Center, Houston, Texas, USA. * Alanna C Morrison * Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA. * Santhi K Ganesh * Center for Population Studies, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA. * Shih-Jen Hwang & * Daniel Levy * Division of Epidemiology and Prevention, Boston University School of Medicine, Boston, Massachusetts, USA. * Ramachandran S Vasan * Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts, USA. * Thomas J Wang * Département de Génétique Médicale, Université de Lausanne, Lausanne, Switzerland. * Sven Bergmann & * Jacques S Beckmann * Swiss Institute of Bioinformatics, Lausanne, Switzerland. * Sven Bergmann * Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. * Peter Vollenweider & * Gérard Waeber * Finnish Institute of Occupational Health, Oulu, Finland. * Jaana Laitinen * National Institute of Health and Welfare, Department of Children, Young People and Families, Oulu, Finland. * Anneli Pouta * Institute of Clinical Medicine, Obstetrics and Gynaecology, University of Oulu, Oulu, Finland. * Anneli Pouta * Department of Physiatrics, Lapland Central Hospital, Rovaniemi, Finland. * Paavo Zitting * Avon Longitudinal Study of Parents and Children (ALSPAC) Laboratory, Department of Social Medicine, University of Bristol, Bristol, UK. * Wendy L McArdle * Institute of Pharmacology, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany. * Heyo K Kroemer * Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany. * Uwe Völker * Institute for Community Medicine, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany. * Henry Völzke * Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA. * Nicole L Glazer * National Institute of Aging's Laboratory for Epidemiology, Demography and Biometry, Bethesda, Maryland, USA. * Tamara B Harris * Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. * Inês Barroso, * So-Youn Shin & * Nicole Soranzo * University of Cambridge Metabolic Research Labs, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. * Inês Barroso * Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK. * Kay-Tee Khaw * U557 Institut National de la Santé et de la Recherche Médicale, Paris, France. * Pilar Galan & * Serge Hercberg * U1125 Institut National de la Recherche Agronomique, Paris, France. * Pilar Galan & * Serge Hercberg * Université Paris 13, Bobigny, France. * Pilar Galan & * Serge Hercberg * Department of Statistics, Pontificia Universidad Catolica de Chile, Santiago, Chile. * Susana Eyheramendy * Department of Psychiatry/EMGO Institute/Neuroscience Campus, VU University Medical Centre, Amsterdam, The Netherlands. * Brenda W Penninx * 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 Clinical Sciences, Diabetes and Endocrinology Research Unit, Lund University, University Hospital Malmö, Malmö, Sweden. * Leif Groop * Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. * Benjamin F Voight, * David Altshuler & * Christopher Newton-Cheh * Department of Clinical Sciences, Hypertension and Cardiovascular Diseases, University Hospital Malmö, Lund University, Malmö, Sweden. * Olle Melander * National Heart, Lung, and Blood Institute and its Framingham Heart Study, Framingham, Massachusetts, USA. * Christopher J O'Donnell * Department of Chronic Disease Prevention, THL-National Institute for Health and Welfare, Helsinki, Finland. * Veikko Salomaa * Institute for Maternal and Child Health-Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) 'Burlo Garofolo'—Trieste, Italy. * Antonella Fabretto, * Flavio Faletra, * Sheila Ulivi & * Paolo Gasparini * National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. * Francis S Collins * Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. * Richard N Bergman * Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia. * John P Beilby * Molecular Genetics, PathWest Laboratory Medicine, Nedlands, Western Australia, Australia. * John P Beilby * Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia. * John P Beilby, * Joseph Hung, * A William Musk & * Lyle J Palmer * School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia. * Joseph Hung * School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia. * A William Musk * Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia. * A William Musk * Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. * Anders Hamsten * Department of Neurology Section of Special Neurology, Medical University Graz, Graz, Austria. * Marisa Loitfelder & * Reinhold Schmidt * National Institute of Aging's Laboratory of Neurogenetics, Bethesda, Maryland, USA. * Dena Hernandez & * Andrew Singleton * Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, Maryland, USA. * Samer S Najjar * Cardiovascular Research Institute, MedStar Health Research Institute, Washington Hospital Center, Washington DC, USA. * Samer S Najjar * Tuscany Regional Health Agency, Florence, Italy. * Anna Maria Corsi * EMGO+ institute, Department of Biological Psychology, VU University, Amsterdam, The Netherlands. * Eco J C de Geus, * Gonneke Willemsen & * Dorret I Boomsma * Amgen, Cambridge, Massachusetts, USA. * Alex N Parker * Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland. * Brendan Buckley * Institute of Cardiovascular and Medical Sciences, School of Medicine, University of Glasgow, Glasgow, UK. * David Stott * Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Monserrato, Italy. * Marco Orru & * Manuela Uda * Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. * Melanie M van der Klauw * National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, UK. * James Scott & * Jaspal S Kooner * Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA. * Gregory L Burke * Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland. * Mika Kähönen * Department of Medicine, University of Turku and Turku University Hospital, Turku, Finland. * Jorma Viikari * Institute of Epidemiology I, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. * Angela Döring & * H-Erich Wichmann * Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany. * Angela Döring * Institute of Human Genetics, Helmholtz Zentrum München–German Research Centre for Environmental Health, Neuherberg, Germany. * Thomas Meitinger * Institute of Human Genetics, Technische Universität München, Munich, Germany. * Thomas Meitinger * Geriatric Medicine Unit, The University of Edinburgh, Royal Victoria, Edinburgh, UK. * John M Starr * Cardiovascular Disease Franchise, Merck Research Laboratory, Rahway, New Jersey, USA. * Andrew Plump * Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands. * Jan H Lindeman * Leiden Genome Technology Center, Leiden University Medical Center, Leiden, The Netherlands. * Peter A C 't Hoen * Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany. * Inke R König & * Michael Preuss * German Cancer Research Center, Division of Clinical Epidemiology and Aging Research, Heidelberg, Germany. * Janine F Felix * Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford, UK. * Robert Clarke & * Jemma C Hopewell * Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA. * Stéphanie Debette * Boston University School of Public Health, Boston, Massachusetts, USA. * Anita L DeStefano * Brown Foundation Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA. * Myriam Fornage * Cardiovascular Engineering, Inc., Norwood, Massachusetts, USA. * Gary F Mitchell * Department of Epidemiology, University of Washington, Seattle, Washington, USA. * Nicholas L Smith, * David Siscovick & * Bruce M Psaty * Seattle Epidemiologic Research and Information, Center of the Department of Veterans Affairs Office of Research and Development, Seattle, Washington, USA. * Nicholas L Smith * Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA. * Nicholas L Smith & * Bruce M Psaty * deCODE genetics Inc. Reykjavik, Iceland. * Hilma Holm, * Kari Stefansson, * Gudmar Thorleifsson & * Unnur Thorsteinsdottir * Faculty of Medicine, University of Iceland, Reykjavik, Iceland. * Kari Stefansson & * Unnur Thorsteinsdottir * Leicester National Institute of Health Research (NIHR) Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, UK. * Nilesh J Samani * Medizinische Klinik II, Universität zu Lübeck, Lübeck, Germany. * Michael Preuss & * Jeanette Erdmann * Croatian Centre for Global Health, University of Split Medical School, Split, Croatia. * Igor Rudan * Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität and Klinikum Grosshadern, Munich, Germany. * H-Erich Wichmann * Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku and the Department of Clinical Physiology, Turku University Hospital, Turku, Finland. * Olli T Raitakari * Columbia University, New York, New York, USA. * Walter Palmas * Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. * Ronald P Stolk * Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands. * J Wouter Jukema * Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands. * J Wouter Jukema * Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy. * Stefania Bandinelli * Ontario Institute for Cancer Research, Toronto, Ontario, Canada. * Lyle J Palmer * Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada. * Lyle J Palmer * National Institute for Health and Welfare, Diabetes Prevention Unit, Helsinki, Finland. * Jaakko Tuomilehto * Hjelt Institute, Department of Public Health, University of Helsinki, Helsinki, Finland. * Jaakko Tuomilehto * South Ostrobothnia Central Hospital, Seinajoki, Finland. * Jaakko Tuomilehto * Institute of Human Genetics, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany. * Arne Pfeufer * Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany. * Arne Pfeufer * Department of Medicine, University of Washington, Seattle, Washington, USA. * David Siscovick * Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. * David Altshuler * Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. * David Altshuler * Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. * David Altshuler * Institute of Molecular Genetics–Consiglio Nazionale delle Ricerche (CNR), Pavia, Italy. * Daniela Toniolo * U872 Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, Paris, France. * Pierre Meneton * Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands. * Ben A Oostra * National Institute of Aging's Laboratory for Epidemiology, Demography and Biometry, Bethesda, Maryland, USA. * Lenore Launer * Institute of Physiology, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany. * Rainer Rettig * Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. * Jacques S Beckmann * Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands. * Ko Willems van Dijk * Human Genetics Center, Houston, Texas, USA. * Eric Boerwinkle * Division of Cardiology, Brigham and Women's Hospital, Boston, Massachusetts, USA. * Paul M Ridker * Institute of Health Sciences, University of Oulu, Oulu, Finland. * Marjo-Riitta Jarvelin * Biocenter, University of Oulu, Oulu, Finland. * Marjo-Riitta Jarvelin * Department of Health Services, University of Washington, Seattle, Washington, USA. * Bruce M Psaty * Department of Psychiatry, Washington University in St. Louis, School of Medicine, Saint Louis, Missouri, USA. * Dabeeru C Rao * Department of Mathematics, Washington University in St. Louis, School of Medicine, Saint Louis, Missouri, USA. * Dabeeru C Rao * MRC-Health Protection Agency (HPA) Centre for Environment and Health, Imperial College London, London, UK. * Paul Elliott * Centre of Medical Systems Biology, Erasmus University Medical Center, Rotterdam, The Netherlands. * Cornelia M van Duijn Consortia * LifeLines Cohort Study * EchoGen consortium * AortaGen Consortium * CHARGE Consortium Heart Failure Working Group * KidneyGen consortium * CKDGen consortium * Cardiogenics consortium * CardioGram Contributions M.J.C., P.E. (co-chair), T.J., P.B.M., P.F.O., M.D.T. (co-chair), C.M.v.D. (co-chair), G.C.V., L.V.W. G.R.A., M. Bochud, M. Boehnke, M.J.C. (co-chair), A.C., G.B.E., P.E., T.B.H., M.-R.J., A.D.J., T.J., M.G.L., L.L., D.L. (co-chair), P.B.M.(co-chair), C.N.-C. (co-chair), B.M.P., K.M.R., A.V.S., M.D.T., C.M.v.D., G.C.V. L.V.W., G.C.V., P.F.O., T.J. V.E., P.H., A.D.J., D.L., J.H.L., C.P.N., A. Plump, P.A.C.'t H., K.W.v.D. AGES: T.A., V.G., T.B.H., L.L., A.V.S. AortaGen Consortium: G.F.M. ARIC: E.B., A.C., S.K.G. ASPS: H. Schmidt, R.S. BLSA: L.F. B58C-T1DGC: D.P.S. B58C-WTCCC: D.P.S. BHS: L.J.P. CARDIoGRAM Consortium: N.J.S. C4D Consortium: R. Clarke, CHS: J.C.B., N.L.G., B.M.P., K.M.R., K.D.T. CHARGE Consortium Heart Failure Working Group: N.L.S. CoLaus: V.M., P. Vollenweider, G. Waeber CROATIA-Korcula: C.H. CROATIA-Split: M. Boban, I.R. CROATIA-Vis: A.F.W. DeCode Genetics: H.H., K.S., G.T., U.T. DGI controls: D.A., L.G., C.N.-C. ENGAGE: J.E., I.R.K. EGCUT: H.A., A.M. EPIC:! K.-T.K. ERF: B.A.O. Fenland: N.J.W. FUSION: M. Boehnke, F.S.C., R.N.B., J.T. INGI CARL: A.P.d'A., P. Gasparini INGI-FVG: A.P.d'A., P. Gasparini INCHIANTI: S. Bandinelli., Y.M. KORA S3: C.G., M. Laan, E.O. KORA F4: T.M., H.-E.W. LifeLines: R.P.S., M.M.v.d.K. LOLIPOP: J.C.C., P.E., J.S.K. LBC1921/LBC1936: I.J.D., J.M.S. MICROS: A. Pfeufer MESA: G.L.B., X.G., W.P. MIGen controls: O.M., C.J.O., V.S., D. Siscovick NESDA: B.W.P., H. Snieder NEURO-CHARGE Consortium: M. Breteler, M. Fornage NFBC1966: M.-R.J., P.Z. NSPHS: U.B.G. NTR: D.I.B., E.J.C.d.G. ORCADES: H.C., J.F.W. PROCARDIS controls: M. Farrall, A. Hamsten, J.F.P., H.W. PROSPER/PHASE: B.B., J.W.J., D. Stott RSI/RSII/RSIII: A. Hofman, C.M.v.D., J.C.M.W. SardiNIA: G.R.A., M.U. SHIP: M.D., H.K.K., R.R., U.V., H.V. SUVIMAX: P. Galan, S. Hercberg, P.M. TwinsUK: T.D.S. WGHS: P.M.R. YFS: M.K., T.L., O.T.R., J.V. AGES: T.A., V.G., T.B.H., L.L. ARIC: A.C., S.K.G., A.C.M., D.C.R. ASPS: M. Loitfelder, R.S. BLSA: S.S.N. B58C-T1DGC: D! .P.S. B58C-WTCCC: D.P.S. BHS: J.P.B., J.H. C4D Consortium: R. ! Clarke, J.C.H. CHS: B.M.P. CoLaus: M. Bochud, V.M., P. Vollenweider CROATIA-Korcula: C.H., O.P. CROATIA-Split: M. Boban, I.R. DGI controls: L.G., C.N.-C. EGCUT: H.A., A.K., A.M., M.-L.T. EPIC: N.J.W. Fenland: N.J.W. FHS: S.-J.H., M.G.L., D.L., R.S.V., T.J.W. FUSION: J.T. INGI CARL: A.F., F.F., P. Gasparini, S.U. INGI FVG: A.F., F.F., P. Gasparini, S.U. INGI-Val Borbera: C. Masciullo, C.S., D.T. INCHIANTI: A.M.C. KORA S3: C.G. KORA F4: A.D. LifeLines: M.M.v.d.K. LOLIPOP: J.C.C., J.S.K., J.S. LBC1921/LBC1936: I.J.D., L.M.L., J.M.S. MICROS: M. Facheris, A. Pfeufer MESA: G.L.B., X.G., W.P. MIGen controls: G.L., O.M., C.J.O., V.S., D. Siscovick NESDA: X. Lu, I.M.N., B.W.P., H. Snieder NEURO-CHARGE Consortium: M. Breteler, S.D., A.L.D., M. Fornage NFBC1966: P.E., M.-R.J., J. Laitinen, A. Pouta, P.Z. NSPHS: U.B.G. NTR: D.I.B., E.J.C.d.G., G. Willemsen ORCADES: S.H.W., J.F.W. PROCARDIS controls: J.F.P. PROSPER/PHASE: D. Stott, S.T. RSI/RSII/RSIII: F.U.S.M.-R., E.J.G.S., C.M.v.D., G! .C.V., J.C.M.W. SardiNIA: M.O., M.U. SHIP: M.D., R.R., H.V. SUVIMAX: P. Galan, M. Lathrop TwinsUK: T.D.S. WGHS: P.M.R. YFS: M.K., T.L., O.T.R., J.V. AGES: A.V.S. ARIC: A.C., G.B.E., S.K.G., A.C.M., D.C.R., G.S. ASPS: P. Gider, H. Schmidt, M.Z. BLSA: D. Hernandez B58C-T1DGC: S. Heath, W.L.M. B58C-WTCCC: W.L.M. BHS: J.P.B., R.J.W. C4D Consortium: J.C.H., H.O. CHS: J.C.B., N.L.G., K.D.T. CoLaus: V.M., P. Vollenweider CROATIA-Korcula: C.H., O.P. CROATIA-Split: I.R. CROATIA-Vis: V.V. DGI controls: D.A., B.F.V. EGCUT: T.E., T.H. EPIC: N.J.W. Fenland: R.J.F.L., J. Luan, N.J.W. FHS: S.-J.H., M.G.L. FUSION: F.S.C. INGI CARL: A.P.d'A. INGI FVG: A.P.d'A. INGI Val Borbera: C. Masciullo, C.S., D.T. INCHIANTI: A.S. KORA S3: C.G., M. Laan, E.O. KORA F4: T.M., H.-E.W. LifeLines: B.Z.A. LOLIPOP: J.C.C., J.S.K., J.S., W.Z. LBC1921/LBC1936: G.D., I.J.D. MICROS: I.P. MESA: G.L.B., Y.-D.I.C., X.G. MIGen controls: G.L., O.M., C.J.O., V.S., D.S. NESDA: J.F., X. Lu, I.M.N., B.W.P., H. Snieder NFBC! 1966: P.E., M.-R.J., J. Laitinen, P.Z. NTR: D.I.B., E.J.C.d.G., J.-J.H.! , G. Willemsen ORCADES: H.C., J.F.W. PROCARDIS controls: A.G., J.F.P. PROSPER/PHASE: S.T. RSI/RSII/RSIII: F.R., A.G.U. SardiNIA: G.R.A. SHIP: H.K.K., U.V., H.V. SUVIMAX: S. Heath, M. Lathrop TwinsUK: M.M., S.-Y.S., N.S., F.Z. WGHS: D.I.C., A.N.P. YFS: T.L., O.T.R. AGES: T.A., A.V.S. ARIC: A.C., G.B.E., A.C.M., V.P., D.C.R., G.S. ASPS: P. Gider, H. Schmidt, M.Z. BLSA: T.T. B58C-T1DGC: D.P.S. B58C-WTCCC: D. Hadley, D.P.S. BHS: A.W.M., L.J.P., R.J.W. C4D Consortium: J.C.H., H.O., CHS: J.C.B., N.L.G., K.M.R. CoLaus: J.S.B., S. Bergmann, M. Bochud, T.J. CROATIA-Korcula: C.H., O.P. CROATIA-Split: C.H. CROATIA-Vis: V.V. DGI controls: P.A., C.N.-C., B.F.V. EchoGen Consortium: J.F.F. EGCUT: T.E., T.H. ENGAGE: M.P. EPIC: I.B., R.J.F.L., N.J.W., J.H.Z. ERF: A.C.J.W.J., Y.A. Fenland: R.J.F.L., J. Luan FHS: S.-J.H., M.G.L. FUSION: A.U.J. INGI CARL: N.P. INGI FVG: N.P. INGI Val Borbera: T.C., G.P., C.S., D.T. KORA S3: S.E., S.S. KORA F4: B.K. LifeLines: B.Z.A. LOLIPOP: J.C.C., J.S.K., X.! Li, J.S., W.Z. LBC1921/LBC1936: L.M.L. MICROS: F.D.G.M. MESA: Y-D.I.C., X.G., W.P. MIGen controls: G.L. NESDA: J.F., X. Lu NEURO-CHARGE Consortium: S.D., A.L.D., M. Fornage NFBC1966: P.F.O. NSPHS:W.I. NTR: J.-J.H. ORCADES: P.N., S.H.W., J.F.W. PROCARDIS controls: M. Farrall, A.G., J.F.P. PROSPER/PHASE: J.W.J., S.T. RSI/RSII/RSIII: N.A., S.K., C.M.v.D., G.C.V. SardiNIA: J.L.B.-G. SHIP: U.V. SUVIMAX: T.J., P.M. TwinsUK: N.S., F.Z. WGHS: D.I.C., L.M.R., YFS: T.L., O.T.R. A list of members is provided in the Supplementary Note. LifeLines Cohort Study EchoGen consortium AortaGen Consortium CHARGE Consortium Heart Failure Working Group KidneyGen consortium CKDGen consortium Cardiogenics consortium CardioGram Competing financial interests A.C. is managed by Johns Hopkins Medicine. I.B. and spouse own stock in Incyte Ltd and GlaxoSmithKline. A.N.P. is an employee of Amgen. G.F.M. is owner of Cardiovascular Engineering, Inc, a company that designs and manufactures devices that measure vascular stiffness. The company uses these devices in clinical studies that evaluate the effects of diseases and interventions on vascular stiffness. V.M. is an employee of GlaxoSmithKline plc. A. Plump is an employee of Merck and Co, Inc. 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• Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia
  - Nat Genet 43(10):1012-1017 (2011)
  Nature Genetics | Letter Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia * Christopher N Hahn1, 2 * Chan-Eng Chong1, 2, 14 * Catherine L Carmichael3, 14 * Ella J Wilkins3, 13 * Peter J Brautigan1 * Xiao-Chun Li1 * Milena Babic1 * Ming Lin1 * Amandine Carmagnac3 * Young K Lee1 * Chung H Kok4, 5 * Lucia Gagliardi1 * Kathryn L Friend6 * Paul G Ekert7 * Carolyn M Butcher4, 5 * Anna L Brown5 * Ian D Lewis2, 5 * L Bik To2, 5 * Andrew E Timms8 * Jan Storek9 * Sarah Moore1 * Meryl Altree10 * Robert Escher3, 13 * Peter G Bardy5 * Graeme K Suthers10, 11 * Richard J D'Andrea2, 4, 5, 15 * Marshall S Horwitz8 * Hamish S Scott1, 2, 3, 12, 15 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:1012–1017Year published:(2011)DOI:doi:10.1038/ng.913Received11 May 2011Accepted29 July 2011Published online04 September 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg We report the discovery of GATA2 as a new myelodysplastic syndrome (MDS)-acute myeloid leukemia (AML) predisposition gene. We found the same, previously unidentified heterozygous c.1061C>T (p.Thr354Met) missense mutation in the GATA2 transcription factor gene segregating with the multigenerational transmission of MDS-AML in three families and a GATA2 c.1063_1065delACA (p.Thr355del) mutation at an adjacent codon in a fourth MDS family. The resulting alterations reside within the second zinc finger of GATA2, which mediates DNA-binding and protein-protein interactions. We show differential effects of the mutations on the transactivation of target genes, cellular differentiation, apoptosis and global gene expression. Identification of such predisposing genes to familial forms of MDS and AML is critical for more effective diagnosis and prognosis, counseling, selection of related bone marrow transplant donors and development of therapies. View full text Figures at a glance * Figure 1: Identification of new germline p.Thr354Met and p.Thr355del variants in the highly conserved zinc finger 2 domain of GATA2 that is associated with MDS-AML. () Pedigrees containing the p.Thr354Met and p.Thr355del variants. One family from Australia (pedigree 1) and two families from the United States (pedigrees 2 and 3) show the p.Thr354Met variant segregating with MDS-AML, and one family from the United States (pedigree 4) has a p.Thr355del variant that segregates with MDS. The genotype of tested individuals is shown: T354 (Thr354, Thr354) and T354M (Thr354, Met354). () Domain structure of GATA2 showing the positions of the alterations. The positions of the p.Thr354Met, p.Thr355del, AML-M5 (ref. 7) (green) and CML blast crisis6 (black) alterations are shown with respect to zinc finger (ZF) 1 and 2, the transactivation domain (TA) and the nuclear localization signal (NLS). () The zinc finger 2 (ZF2) domain of GATA2 and GATA3 contains alterations associated with leukemia and breast cancer. The primary sequence is that of human GATA2, with the two alternative residues in GATA3 ZF2 shown (light gray with black letters). The positio! ns of p.Thr354Met and p.Thr355del are highlighted, along with alterations found in GATA2 in AML-M5 (ref. 7) (green) and CML blast crisis6 (black), and alterations in GATA3 in breast cancer (summarized in ref. 8) (mutated residues in the corresponding GATA3 ZF2 are gray with white letters). * Figure 2: Subcellular localization and DNA binding properties of wild-type and mutant GATA2. We transiently transfected HEK293 cells with empty vector (EV) (pCMV-XL6 empty vector), wild-type (WT), p.Thr354Met, p.Thr355del or p.Leu359Val and harvested them after 24 h. () Protein blot analysis of GATA2 expression in nuclear lysates. We prepared the nuclear lysates and performed protein blots probing for GATA2. () We stained the cells for GATA2 (pink) and DAPI (blue). Scale bars, 10 μm. () Electromobility shift assay (EMSA) of wild-type and mutant GATA2. We prepared the nuclear lysates and bound them to the TCRδ enhancer (which contains the GATA binding site) oligonucleotide in the absence or presence of 200-fold unlabeled competitor oligonucleotide (D, human TCRδ enhancer; C, GATA consensus; G, granulocyte–macrophage colony stimulating factor (GM-CSF) promoter). We visualized the probes using chemiluminescence (top). GATA2 & NS corresponds to a band that contains both GATA2 and a non-specific protein. To visualize GATA2 alone, we performed an EMSA-protein blot pr! obing with polyclonal α-GATA2 antibody (bottom), which shows the level of binding of wild-type and mutant GATA2. A neutralizing α-GATA2 antibody in the far right lane removed GATA2 but not the non-specific binding protein (top), and the specificity of GATA2 is confirmed below. * Figure 3: p.Thr354Met and Thr355del cause altered transactivation through target GATA2 response elements. Thr354Met and Thr355del act as a loss-of-function alterations on GATA2 target promoter and enhancer elements. We cotransfected HEK293 cells with (i) GATA2-responsive CD34 (mut, CD34 enhancer with GATA binding sites mutated32) () and RUNX1 () enhancer elements linked to a luciferase (LUC) reporter, and (ii) GATA2 (wild-type, Thr354Met, Thr355del or Leu359Val) expression constructs or pCMV6-XL6 empty vector (EV). Similarly, we cotransfected Cos-7 cells using LYL1 promoter luciferase as a reporter (). After 20 h, we harvested the cells, performed luciferase assays and plotted them as fold change (mean ± s.e.m.) compared to the empty vector control. The pairwise comparisons are shown (*P < 0.05, for , and n = 3). () Thr354Met and Thr355del act as dominant negative alterations over wild-type GATA2. We cotransfected HEK293 cells with CD34 enhancer-luciferase reporter and equivalent mole ratios of wild-type to Thr354Met or Thr355del. After 20 h, we harvested the cells and performe! d luciferase assays. The pairwise comparisons are shown (*P < 0.05, n = 3; NS, not significant). () Thr354Met has reduced ability to co-activate the CSF1R (M-CSFR) promoter with PU.1. We cotransfected Cos-7 cells with CSF1R promoter-luciferase reporter, PU.1 expression construct and wild-type, Thr354Met, Thr355del or Leu359Val expression constructs or empty vector. After 20 h, we performed luciferase assays and plotted them as fold change compared to empty vector. Pairwise comparisons are shown (*P < 0.05 compared to wild-type plus PU.1; **P < 0.05 compared to wild-type plus PU.1, but the results were not significant when compared to Thr354Met or Thr355del plus PU.1). In all comparisons, we used a Student's t-test. * Figure 4: p.Thr354Met inhibits differentiation and apoptosis while allowing accumulation of cells in the presence of ATRA-induced differentiation. We treated HL-60 cells carrying stably transduced 4HT-regulatable GATA2 (wild-type, Thr354Met, Thr355del and Leu359Val) or empty vector (EV) with or without 30 nM 4HT for 24 h and then with or without 2 μM ATRA for 6 days. (–) Differentiation of HL-60 cells into granulocytes. We measured differentiation by fluorescence-activated cell sorting (FACS) analysis for percentage of CD11b-positive cells (values are mean ± s.e.m.) (Supplementary Fig. 7b). () Cell numbers following differentiation. We counted cells after 6 days (values are mean ± s.e.m.). (–) Apoptosis following differentiation with ATRA. We analyzed cells using FACS following staining with fluorescein isothiocyanate anti-Annexin V and propidium iodide (PI). Cells were Annexin V+, PI− (black) or Annexin V+, PI+ (white). Shown are indicative FACS plots (Supplementary Fig. 7c). () −4HT, –ATRA. (,,) +4HT, –ATRA. (,,) −4HT, +ATRA. (,,) +4HT, +ATRA. *P < 0.05; **P < 0.01, compared to wild-type. In all comp! arisons, we used a Student's t-test. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions Entrez Nucleotide * NM_032638.4 Gene Expression Omnibus * GSE29276 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Chan-Eng Chong & * Catherine L Carmichael Affiliations * Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia. * Christopher N Hahn, * Chan-Eng Chong, * Peter J Brautigan, * Xiao-Chun Li, * Milena Babic, * Ming Lin, * Young K Lee, * Lucia Gagliardi, * Sarah Moore & * Hamish S Scott * School of Medicine, University of Adelaide, South Australia, Australia. * Christopher N Hahn, * Chan-Eng Chong, * Ian D Lewis, * L Bik To, * Richard J D'Andrea & * Hamish S Scott * Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. * Catherine L Carmichael, * Ella J Wilkins, * Amandine Carmagnac, * Robert Escher & * Hamish S Scott * Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville, South Australia, Australia. * Chung H Kok, * Carolyn M Butcher & * Richard J D'Andrea * Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia. * Chung H Kok, * Carolyn M Butcher, * Anna L Brown, * Ian D Lewis, * L Bik To, * Peter G Bardy & * Richard J D'Andrea * Department of Paediatric and Reproductive Genetics, SA Pathology, Adelaide, South Australia, Australia. * Kathryn L Friend * Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. * Paul G Ekert * Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA. * Andrew E Timms & * Marshall S Horwitz * Department of Medicine, University of Calgary, Calgary, Alberta, Canada. * Jan Storek * SA Clinical Genetics Service, SA Pathology, Adelaide, South Australia, Australia. * Meryl Altree & * Graeme K Suthers * Department of Paediatrics, University of Adelaide, Adelaide, South Australia, Australia. * Graeme K Suthers * School of Molecular and Biomedical Science, University of Adelaide, South Australia, Australia. * Hamish S Scott * Present addresses: Neurogenetics Laboratory, Howard Florey Institute, Parkville, Victoria, Australia (E.J.W.) and Medical Clinic, Regional Hospital Emmental, Burgdorf, Switzerland (R.E.). * Ella J Wilkins & * Robert Escher * These authors jointly directed this work. * Richard J D'Andrea & * Hamish S Scott Contributions C.N.H., R.J.D., M.S.H. and H.S.S. managed the project. C.N.H., C.L.C., E.J.W., C.-E.C., P.J.B., X.-C.L., M.B., M.L., A.C., Y.K.L., C.M.B., K.L.F. and A.E.T. performed the experiments. C.H.K. and R.J.D. performed structural modeling, and C.N.H., C.H.K. and L.G. performed data analysis. L.B.T., M.A., J.S., P.G.B., G.K.S., R.J.D., M.S.H. and H.S.S. collected families with MDS and/or AML and provided clinical data and samples. R.E. and P.G.E. participated in experimental design and provided critical reagents. A.L.B., I.D.L., S.M. and L.B.T. provided sporadic AML samples and correlative clinical data. C.N.H., R.J.D., M.S.H. and H.S.S. wrote the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Hamish S Scott Author Details * Christopher N Hahn Search for this author in: * NPG journals * PubMed * Google Scholar * Chan-Eng Chong Search for this author in: * NPG journals * PubMed * Google Scholar * Catherine L Carmichael Search for this author in: * NPG journals * PubMed * Google Scholar * Ella J Wilkins Search for this author in: * NPG journals * PubMed * Google Scholar * Peter J Brautigan Search for this author in: * NPG journals * PubMed * Google Scholar * Xiao-Chun Li Search for this author in: * NPG journals * PubMed * Google Scholar * Milena Babic Search for this author in: * NPG journals * PubMed * Google Scholar * Ming Lin Search for this author in: * NPG journals * PubMed * Google Scholar * Amandine Carmagnac Search for this author in: * NPG journals * PubMed * Google Scholar * Young K Lee Search for this author in: * NPG journals * PubMed * Google Scholar * Chung H Kok Search for this author in: * NPG journals * PubMed * Google Scholar * Lucia Gagliardi Search for this author in: * NPG journals * PubMed * Google Scholar * Kathryn L Friend Search for this author in: * NPG journals * PubMed * Google Scholar * Paul G Ekert Search for this author in: * NPG journals * PubMed * Google Scholar * Carolyn M Butcher Search for this author in: * NPG journals * PubMed * Google Scholar * Anna L Brown Search for this author in: * NPG journals * PubMed * Google Scholar * Ian D Lewis Search for this author in: * NPG journals * PubMed * Google Scholar * L Bik To Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew E Timms Search for this author in: * NPG journals * PubMed * Google Scholar * Jan Storek Search for this author in: * NPG journals * PubMed * Google Scholar * Sarah Moore Search for this author in: * NPG journals * PubMed * Google Scholar * Meryl Altree Search for this author in: * NPG journals * PubMed * Google Scholar * Robert Escher Search for this author in: * NPG journals * PubMed * Google Scholar * Peter G Bardy Search for this author in: * NPG journals * PubMed * Google Scholar * Graeme K Suthers Search for this author in: * NPG journals * PubMed * Google Scholar * Richard J D'Andrea Search for this author in: * NPG journals * PubMed * Google Scholar * Marshall S Horwitz Search for this author in: * NPG journals * PubMed * Google Scholar * Hamish S Scott Contact Hamish S Scott 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 Figures 1–8, Supplementary Tables 1–13 and Supplementary Note. 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• Germline mutations in BAP1 predispose to melanocytic tumors
  - Nat Genet 43(10):1018-1021 (2011)
  Nature Genetics | Letter Germline mutations in BAP1 predispose to melanocytic tumors * Thomas Wiesner1, 2 * Anna C Obenauf3, 4 * Rajmohan Murali2 * Isabella Fried1 * Klaus G Griewank2 * Peter Ulz3 * Christian Windpassinger3 * Werner Wackernagel5 * Shea Loy2 * Ingrid Wolf1 * Agnes Viale6 * Alex E Lash7 * Mono Pirun7 * Nicholas D Socci7 * Arno Rütten8 * Gabriele Palmedo8 * David Abramson9 * Kenneth Offit4, 10 * Arthur Ott11 * Jürgen C Becker1 * Lorenzo Cerroni1 * Heinz Kutzner8 * Boris C Bastian2, 12, 13 * Michael R Speicher3, 13 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:1018–1021Year published:(2011)DOI:doi:10.1038/ng.910Received16 February 2011Accepted22 July 2011Published online28 August 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Common acquired melanocytic nevi are benign neoplasms that are composed of small, uniform melanocytes and are typically present as flat or slightly elevated pigmented lesions on the skin. We describe two families with a new autosomal dominant syndrome characterized by multiple, skin-colored, elevated melanocytic tumors. In contrast to common acquired nevi, the melanocytic neoplasms in affected family members ranged histopathologically from epithelioid nevi to atypical melanocytic proliferations that showed overlapping features with melanoma. Some affected individuals developed uveal or cutaneous melanomas. Segregating with this phenotype, we found inactivating germline mutations of BAP1, which encodes a ubiquitin carboxy-terminal hydrolase. The majority of melanocytic neoplasms lost the remaining wild-type allele of BAP1 by various somatic alterations. In addition, we found BAP1 mutations in a subset of sporadic melanocytic neoplasms showing histological similarities to the ! familial tumors. These findings suggest that loss of BAP1 is associated with a clinically and morphologically distinct type of melanocytic neoplasm. View full text Figures at a glance * Figure 1: Pedigrees and clinical phenotypes of two affected families. Left panel shows family 1; right panel shows family 2. () Pedigrees. Ages of onset in years of the first melanoma or melanocytic tumor of uncertain malignant potential are written below the symbols. Only subjects older than 18 years were tested for mutations. An extended pedigree of family 1 is shown in Supplementary Figure 15. () Representative melanocytic neoplasms from affected individuals (II-4 and II-7 from family 1; III-1 and III-3 from family 2). Note the characteristic inconspicuous, skin-colored to reddish-brown, dome-shaped appearance. Scale bars, 1 mm. () Histopathology of representative melanocytic tumors from both families showing relatively symmetrical intradermal proliferations of large epithelioid melanocytes with abundant cytoplasm and enlarged, irregularly shaped vesicular nuclei, some with prominent nucleoli. Scale bars, 50 μm. Scale bars inset, 1 mm. * Figure 2: Identification of BAP1 germline mutations. () aCGH profiles of recurrent deletions affecting chromosome 3 in the melanocytic neoplasms of family 1. The two top aCGH profiles illustrate deletions of the entire chromosome 3, whereas the other profiles show focal deletions in 3p21. The minimally deleted region (black arrows) encompassed approximately 6 Mb. The next to last profile shows an additional loss in chromosome 11 and the last profile a gain of chromosome 15. () Gene structure of BAP1 and germline mutations observed in affected individuals from families 1 and 2. * Figure 3: Biallelic BAP1 loss is associated with characteristic histological features in familial melanocytic neoplasms. (–) A melanocytic neoplasm from individual III-3, family 2 (), presents as a combined lesion with an area of small cells (common acquired nevus) on the left () and an area of large epithelioid cells on the right (). Scale bars in ,, 50 μm. Fluorescence in situ hybridization (red signal: 3p21 (BAP1); orange: 3p25 (control); green: 4p12 (control)) shows loss of BAP1 in the area with large epithelioid melanocytes (inset in : one red BAP1 signal but two orange and green control signals per nucleus; scale bar, 10 μm) but no loss in the region of the common nevus (inset in : two signals of each probe; scale bar, 10 μm). () BAP1 immunohistochemistry at the transition area between common nevus and epithelioid cell area showing a strong nuclear staining in the common nevus component (left) and loss of nuclear staining in the epithelioid component (right). Scale bar, 100 μm. * Figure 4: Progression of nevus to melanoma is associated with loss of BAP1. () Scanning magnification of a sporadic melanoma (M) arising within a nevus (N) (hematoxylin-eosin stain). () Nevus component with bland melanocytes containing monomorphous round and oval-shaped nuclei. Scale bar, 50 μm. () Melanoma component showing melanocytes with large vesicular nuclei and prominent nucleoli. Scale bar, 50 μm. () MIB-1 (Ki-67) immunohistochemistry showing a high proliferation rate in the melanoma compared to the nevus component. Scale bar, 100 μm. () BAP1 immunohistochemistry showing a conspicuous nuclear staining in the nevus contrasted with absent nuclear staining in the melanoma. Scale bar, 100 μm. () aCGH of the nevus component reveals no chromosomal aberrations. The electropherogram shows a BRAF p.Val600Glu mutation and no BAP1 mutation. () aCGH of the melanoma component reveals a focal loss of chromosome region 3p21 spanning the BAP1 locus. The electropherogram shows the same BRAF p.Val600Glu mutation and, in addition, a frameshift mutation of ! the second BAP1 allele. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions Entrez Nucleotide * NM_004656.2 * NM_004333.4 * NM_002072.3 * NM_002067.2 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Boris C Bastian & * Michael R Speicher Affiliations * Department of Dermatology, Medical University of Graz, Graz, Austria. * Thomas Wiesner, * Isabella Fried, * Ingrid Wolf, * Jürgen C Becker & * Lorenzo Cerroni * Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. * Thomas Wiesner, * Rajmohan Murali, * Klaus G Griewank, * Shea Loy & * Boris C Bastian * Institute of Human Genetics, Medical University of Graz, Graz, Austria. * Anna C Obenauf, * Peter Ulz, * Christian Windpassinger & * Michael R Speicher * Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. * Anna C Obenauf & * Kenneth Offit * Department of Ophthalmology, Medical University of Graz, Graz, Austria. * Werner Wackernagel * Genomics Core Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. * Agnes Viale * Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. * Alex E Lash, * Mono Pirun & * Nicholas D Socci * Dermatopathologie, Friedrichshafen, Germany. * Arno Rütten, * Gabriele Palmedo & * Heinz Kutzner * Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. * David Abramson * Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. * Kenneth Offit * Institute of Pathology, Medical University of Graz, Graz, Austria. * Arthur Ott * Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. * Boris C Bastian Contributions Project planning and experimental design: T.W., B.C.B. and M.R.S. Review of clinical phenotypes: T.W., I.F., I.W. and J.C.B. Review of histology and immunohistology: T.W., B.C.B., H.K., R.M., L.C., I.F., A.R. and A.O. FISH analysis: T.W. and G.P. Sample collection: T.W., H.K., W.W., K.O. and D.A. aCGH: T.W. and A.C.O. Linkage analysis: A.C.O. and C.W. Mutation analysis: T.W., P.U. and S.L. Next-generation sequencing and data analysis: T.W., A.V., A.E.L., N.D.S. and M.P. Manuscript writing: T.W., B.C.B., R.M., M.R.S. and K.G.G. Revision of the manuscript: all authors. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Thomas Wiesner or * Boris C Bastian or * Michael R Speicher Author Details * Thomas Wiesner Contact Thomas Wiesner Search for this author in: * NPG journals * PubMed * Google Scholar * Anna C Obenauf Search for this author in: * NPG journals * PubMed * Google Scholar * Rajmohan Murali Search for this author in: * NPG journals * PubMed * Google Scholar * Isabella Fried Search for this author in: * NPG journals * PubMed * Google Scholar * Klaus G Griewank Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Ulz Search for this author in: * NPG journals * PubMed * Google Scholar * Christian Windpassinger Search for this author in: * NPG journals * PubMed * Google Scholar * Werner Wackernagel Search for this author in: * NPG journals * PubMed * Google Scholar * Shea Loy Search for this author in: * NPG journals * PubMed * Google Scholar * Ingrid Wolf Search for this author in: * NPG journals * PubMed * Google Scholar * Agnes Viale Search for this author in: * NPG journals * PubMed * Google Scholar * Alex E Lash Search for this author in: * NPG journals * PubMed * Google Scholar * Mono Pirun Search for this author in: * NPG journals * PubMed * Google Scholar * Nicholas D Socci Search for this author in: * NPG journals * PubMed * Google Scholar * Arno Rütten Search for this author in: * NPG journals * PubMed * Google Scholar * Gabriele Palmedo Search for this author in: * NPG journals * PubMed * Google Scholar * David Abramson Search for this author in: * NPG journals * PubMed * Google Scholar * Kenneth Offit Search for this author in: * NPG journals * PubMed * Google Scholar * Arthur Ott Search for this author in: * NPG journals * PubMed * Google Scholar * Jürgen C Becker Search for this author in: * NPG journals * PubMed * Google Scholar * Lorenzo Cerroni Search for this author in: * NPG journals * PubMed * Google Scholar * Heinz Kutzner Search for this author in: * NPG journals * PubMed * Google Scholar * Boris C Bastian Contact Boris C Bastian Search for this author in: * NPG journals * PubMed * Google Scholar * Michael R Speicher Contact Michael R Speicher Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (12M) Supplementary Figures 1–15 and Supplementary Tables 1–9 Additional data
• Germline BAP1 mutations predispose to malignant mesothelioma
  - Nat Genet 43(10):1022-1025 (2011)
  Nature Genetics | Letter Germline BAP1 mutations predispose to malignant mesothelioma * Joseph R Testa1 * Mitchell Cheung1 * Jianming Pei1 * Jennifer E Below2 * Yinfei Tan1 * Eleonora Sementino1 * Nancy J Cox2, 3 * A Umran Dogan4, 5 * Harvey I Pass6 * Sandra Trusa6 * Mary Hesdorffer7 * Masaki Nasu8, 9 * Amy Powers8 * Zeyana Rivera8, 9 * Sabahattin Comertpay8, 9 * Mika Tanji8, 9 * Giovanni Gaudino8 * Haining Yang8, 10 * Michele Carbone8 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:1022–1025Year published:(2011)DOI:doi:10.1038/ng.912Received06 May 2011Accepted27 July 2011Published online28 August 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma1, and because mesothelioma clustering is observed in some families, we searched for genetic predisposing factors. We discovered germline mutations in the gene encoding BRCA1 associated protein-1 (BAP1) in two families with a high incidence of mesothelioma, and we observed somatic alterations affecting BAP1 in familial mesotheliomas, indicating biallelic inactivation. In addition to mesothelioma, some BAP1 mutation carriers developed uveal melanoma. We also found germline BAP1 mutations in 2 of 26 sporadic mesotheliomas; both individuals with mutant BAP1 were previously diagnosed with uveal melanoma. We also observed somatic truncating BAP1 mutations and aberrant BAP1 expression in sporadic mesotheliomas without germline mutations. These results identify a BAP1-related cancer syndrome that is characterized by mesothelioma and uveal melanoma. We hypothesize that other cancers may also ! be involved and that mesothelioma predominates upon asbestos exposure. These findings will help to identify individuals at high risk of mesothelioma who could be targeted for early intervention. View full text Figures at a glance * Figure 1: Pedigrees of two US families with high incidence of mesothelioma. (,) Pedigrees showing family members with a germline mutation in BAP1, as confirmed by both sequencing and linkage analyses (orange) or by linkage analysis alone (yellow; that is, no DNA was available for sequencing); individuals without the mutation (green) and individuals for whom DNA was unavailable (blue) are also shown. The presence or absence of germline BAP1 mutation is also indicated with + or − symbols, respectively. () Pedigree of family W showing the presence or absence of a germline mutation at the BAP1 consensus splice acceptor site. () Pedigree of family L showing the presence or absence of a germline nonsense mutation. The development of other tumor types (Supplementary Table 1) in these families may also be related to BAP1 germline mutations. In family W, the presence of a case of breast cancer before age 45 and a case of ovarian cancer suggests that the BAP1 mutation may be associated with a hereditary form of breast and ovarian cancer. In family L, the sk! in cancers shown were squamous-cell carcinomas. Available mesothelioma tumor specimens with a germline splice-site mutation and either a somatic 25-bp deletion (W-III-04T), genomic alteration (W-III-06T) or loss of the wild-type BAP1 allele (W-III-08T) are indicated in Supplementary Table 1, as is the homozygous deletion of BAP1 seen in mesothelioma specimen L-III-18T. * Figure 2: Array-CGH analysis of members of the L and W families and schematic diagrams of predicted mutant BAP1 proteins. () Array-CGH showing a focal deletion encompassing BAP1 within a larger 3p deletion (tumor L-III-18T) and an amplicon adjacent to BAP1 locus (tumor W-III-06T). The BAP1 gene resides at chr3:52,435,027–52,444,009, and the Agilent Human 244K chip contains two probes within the BAP1 locus: A_16_P00704764 (chr3:52,438,014–52,438,066) and A_14_P128339 (chr3:52,443,209–52,443,268). In W-III-06T, the two BAP1 probes had log2 ratios indicative of normal diploid DNA copy numbers, whereas the log2 ratios of two probes immediately centromeric of BAP1 showed a transition to a higher copy number, indicating the start of an amplified region at or near the BAP1 promoter (zoomed-in image and further details shown in Supplementary Fig. 6). In L-III-18T, the focal homozygous deletion encompassed the entire BAP1 locus and was ~218 kb. () Schematic diagram of predicted truncations of BAP1 resulting from the germline mutations observed in two families (W and L) with high incidence of mesot! helioma, as well as in two sporadic cases of mesothelioma in individuals who had previously developed uveal melanomas (SP-002; SP-008). * Figure 3: Immunohistochemistry on mesotheliomas from the L and W families shows a lack of BAP1 nuclear expression and only weak, focal cytoplasmic BAP1 staining. () SP-024 denotes sporadic mesothelioma with wild-type BAP1; note the normal nuclear expression of BAP1. (–) W-III-04 (), L-III-18 () and W-III-06 () represent mesotheliomas from individuals with germline BAP1 mutations. Note the lack of nuclear BAP1 expression and weak cytoplasmic staining in –. All magnifications 400×. Scale bar, 100 μm. * Figure 4: BAP1 truncating mutations and aberrant protein expression in sporadic mesothelioma tumor biopsies. () Schematic diagram of predicted truncations of BAP1 in four sporadic mesotheliomas harboring BAP1 mutations. The bracket at left indicates mutations in two different BAP1 alleles in tumor sample SP-015. NLS, nuclear localization signal at the C terminus of BAP1. Frameshift sequences are shown as thinner gray bars. () Immunoblot analysis on whole-tumor cell lysates from the same four sporadic mesotheliomas with somatic BAP1 mutations (lanes 2–5) and from a sporadic tumor lacking a BAP1 mutation (lane 1). Sporadic mesotheliomas with somatic BAP1 mutations show decreased expression of BAP1 compared to that seen in tumors without BAP1 mutation. Note that, in mesotheliomas, whole-tumor cell lysates inevitably contain some normal stromal cells that may be responsible for the faint BAP1 signal detected. Also note the presence of an additional, faster-migrating BAP1 band in the sample shown in lane 4 (SP-013), suggesting the presence of a truncated form of BAP1. The BAP1 protein! products predicted in tumors SP-001 and SP-015 were not observed, suggesting nonsense-mediated mRNA decay. The mutation in tumor SP-018 results in a predicted protein product only 15 residues smaller, which presumably precludes detection of a small change in molecular weight compared to wild-type BAP1. GAPDH was used as a loading control. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions GenBank * NP_004647.1 Author information * Accession codes * Author information * Supplementary information Affiliations * Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA. * Joseph R Testa, * Mitchell Cheung, * Jianming Pei, * Yinfei Tan & * Eleonora Sementino * Department of Medicine, University of Chicago, Chicago, Illinois, USA. * Jennifer E Below & * Nancy J Cox * Department of Human Genetics, University of Chicago, Chicago, Illinois, USA. * Nancy J Cox * Earth Sciences Department, King Fahd University of Petroleum and Minerals, Dhahran, Saudi Arabia. * A Umran Dogan * Department of Chemical and Biochemical Engineering, University of Iowa, Iowa City, Iowa, USA. * A Umran Dogan * New York University, Langone Medical Center and Cancer Center, New York, New York, USA. * Harvey I Pass & * Sandra Trusa * Mesothelioma Applied Research Foundation, Alexandria, Virginia, USA. * Mary Hesdorffer * University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, Hawaii, USA. * Masaki Nasu, * Amy Powers, * Zeyana Rivera, * Sabahattin Comertpay, * Mika Tanji, * Giovanni Gaudino, * Haining Yang & * Michele Carbone * Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, Hawaii, USA. * Masaki Nasu, * Zeyana Rivera, * Sabahattin Comertpay & * Mika Tanji * Department of Pathology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, USA. * Haining Yang Contributions J.R.T. led the team at Fox Chase Cancer Center (FCCC; M. Cheung, J.P., Y.T. and E.S.) that first identified and characterized the BAP1 mutations and genomic alterations in the two families with high incidence of mesothelioma, performed the splicing and functional assays, and discovered BAP1 mutations in sporadic tumors and cell lines. N.J.C. designed and directed the genetic linkage analysis studies performed by J.E.B. H.I.P. treated many of these patients and together with S.T. and M.H. provided the tumor samples, DNA and clinical information. A.U.D. performed the mineralogical studies. M. Carbone conceived the project, assembled the families and the entire research group, diagnosed mesotheliomas and led the team at University of Hawaii Cancer Center (UHCC; M.N., A.P., Z.R., S.C., M.T., G.G. and H.Y.) that confirmed the mutations in the two families and discovered germline and somatic mutations in sporadic mesotheliomas. M.N. led the experimental work conducted by the UHCC ! team. J.R.T. and M. Carbone wrote the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Joseph R Testa or * Michele Carbone Author Details * Joseph R Testa Contact Joseph R Testa Search for this author in: * NPG journals * PubMed * Google Scholar * Mitchell Cheung Search for this author in: * NPG journals * PubMed * Google Scholar * Jianming Pei Search for this author in: * NPG journals * PubMed * Google Scholar * Jennifer E Below Search for this author in: * NPG journals * PubMed * Google Scholar * Yinfei Tan Search for this author in: * NPG journals * PubMed * Google Scholar * Eleonora Sementino Search for this author in: * NPG journals * PubMed * Google Scholar * Nancy J Cox Search for this author in: * NPG journals * PubMed * Google Scholar * A Umran Dogan Search for this author in: * NPG journals * PubMed * Google Scholar * Harvey I Pass Search for this author in: * NPG journals * PubMed * Google Scholar * Sandra Trusa Search for this author in: * NPG journals * PubMed * Google Scholar * Mary Hesdorffer Search for this author in: * NPG journals * PubMed * Google Scholar * Masaki Nasu Search for this author in: * NPG journals * PubMed * Google Scholar * Amy Powers Search for this author in: * NPG journals * PubMed * Google Scholar * Zeyana Rivera Search for this author in: * NPG journals * PubMed * Google Scholar * Sabahattin Comertpay Search for this author in: * NPG journals * PubMed * Google Scholar * Mika Tanji Search for this author in: * NPG journals * PubMed * Google Scholar * Giovanni Gaudino Search for this author in: * NPG journals * PubMed * Google Scholar * Haining Yang Search for this author in: * NPG journals * PubMed * Google Scholar * Michele Carbone Contact Michele Carbone Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (5M) Supplementary Tables 1 and 2 and Supplementary Figures 1–6 Additional data
• Germline deletion of the miR-17~92 cluster causes skeletal and growth defects in humans
  - Nat Genet 43(10):1026-1030 (2011)
  Nature Genetics | Letter Germline deletion of the miR-17~92 cluster causes skeletal and growth defects in humans * Loïc de Pontual1, 2, 10 * Evelyn Yao3, 10 * Patrick Callier4 * Laurence Faivre4 * Valérie Drouin5 * Sandra Cariou1 * Arie Van Haeringen6 * David Geneviève7 * Alice Goldenberg5 * Myriam Oufadem1 * Sylvie Manouvrier8 * Arnold Munnich1, 9 * Joana Alves Vidigal3 * Michel Vekemans1 * Stanislas Lyonnet1, 9 * Alexandra Henrion-Caude1 * Andrea Ventura3, 10 * Jeanne Amiel1, 9, 10 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:1026–1030Year published:(2011)DOI:doi:10.1038/ng.915Received12 April 2011Accepted29 July 2011Published online04 September 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg MicroRNAs (miRNAs) are key regulators of gene expression in animals and plants. Studies in a variety of model organisms show that miRNAs modulate developmental processes. To our knowledge, the only hereditary condition known to be caused by a miRNA is a form of adult-onset non-syndromic deafness1, and no miRNA mutation has yet been found to be responsible for any developmental defect in humans. Here we report the identification of germline hemizygous deletions of MIR17HG, encoding the miR-17~92 polycistronic miRNA cluster, in individuals with microcephaly, short stature and digital abnormalities. We demonstrate that haploinsufficiency of miR-17~92 is responsible for these developmental abnormalities by showing that mice harboring targeted deletion of the miR-17~92 cluster phenocopy several key features of the affected humans. These findings identify a regulatory function for miR-17~92 in growth and skeletal development and represent the first example of an miRNA gene respons! ible for a syndromic developmental defect in humans. View full text Figures at a glance * Figure 1: Clinical features of individuals with 13q31.3 deletions. Clinical features and radiographs of affected individuals from families AO39 and AO70 and subject 248412 showing brachydactyly, brachymesophalangy of the second and fifth fingers (better appreciated on the palmar view, arrows), hypoplastic thumbs of variable severity (asterisks) and cutaneous syndactyly of toes (arrow heads). * Figure 2: Mapping 13q31.3 microdeletions in individuals with Feingold syndrome. () Schematic illustration of the microdeletions identified in families AO39 and AO70 and in individual 248412 from DECIPHER. () Genomic qPCR showing that the microdeletion segregates with disease in families AO70 and AO39. () RT-qPCR showing reduced expression of individual miRNAs encoded by the miR-17~92a cluster in peripheral white blood cells of individuals carrying 13q31.3 microdeletions (n = 3) compared to healthy donors (n = 4). For each miRNA, the mean relative expression and the range of expression (error bars) compared to control donors are shown. * Figure 3: miR-17~92Δ/+ mice display features of Feingold syndrome. () Mice hemizygous for miR-17~92 are smaller than their wild-type littermates. We weighed wild-type (empty circles) and miR-17~92Δ/+ (filled circles) mice at postnatal day 0 (P0) (left panel) or at weaning (3 weeks, right panel). We computed P values using a two-tailed t-test. () Alcian blue and alizarin red staining of wild-type and miR-17~92Δ/+ forelimbs from female age-matched mice. The fifth mesophalanx (arrows) is shorter in hemizygous animals compared to wild-type mice (bar). () Quantification of the relative length of the fifth mesophalanx in wild-type (n = 6) and miR-17~92Δ/+ (n = 10) mouse forelimbs. The ratio between the length of the fifth mesophalanx and the length of the fifth metacarpal bone is plotted. Error bars, s.d. () Lateral (left) and dorsal (right) views of mouse skulls of age-matched wild-type (top) and miR-17~92Δ/+ (bottom) male mice. * Figure 4: Widespread skeletal defects in E18.5 miR-17~92Δ/Δ embryos. () Skeletal staining of the left hand of E18.5 littermate embryos. Notice the absence of the fifth mesophalanx (M) in the forelimb of the miR-17~92Δ/Δ embryo (P, proximal; D, distal). Also notice the delayed ossification of the metacarpal bones and proximal phalanges and the fusion of the first row of carpal bones (red arrowhead) in the mutant embryo. () Lateral views of embryonic skeletons showing delayed ossification of the skull and asymmetric fusions of the first three cervical vertebrae in the knockout animals (arrow). Dorsal () and ventral () views of the skulls of miR-17~92Δ/Δ and wild-type E18.5 embryos showing microcephalia and delayed ossification of occipital, parietal and frontal bones in mutant embryos. Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Loïc de Pontual, * Evelyn Yao, * Andrea Ventura & * Jeanne Amiel Affiliations * Unité INSERM U-781, Université Paris Descartes, Paris, France. * Loïc de Pontual, * Sandra Cariou, * Myriam Oufadem, * Arnold Munnich, * Michel Vekemans, * Stanislas Lyonnet, * Alexandra Henrion-Caude & * Jeanne Amiel * Services de Pédiatrie, Hôpital Jean Verdier, Université Paris XIII, Assistance Publique-Hôpitaux de Paris (AP-HP), Bondy, France. * Loïc de Pontual * Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. * Evelyn Yao, * Joana Alves Vidigal & * Andrea Ventura * Service de Génétique, Hôpital d'enfants, Dijon, France. * Patrick Callier & * Laurence Faivre * Service de Génétique, Hôpital Charles Nicolle, Rouen, France. * Valérie Drouin & * Alice Goldenberg * Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. * Arie Van Haeringen * Service de Génétique, Hôpital Arnaud de Villeneuve, Montpellier, France. * David Geneviève * Service de Génétique Clinique, Hôpital J. de Flandre, Lille, France. * Sylvie Manouvrier * Services de Génétique et Cytogénétique, Hôpital Necker-Enfant Malades, AP-HP, Paris, France. * Arnold Munnich, * Stanislas Lyonnet & * Jeanne Amiel Contributions L.d.P., P.C., S.C. and M.O. performed subject-related experiments. E.Y. performed the analysis of miR-17~92 mutant mice, the ChIP experiments and determined miR-17~92 expression in subjects. J.A.V. determined miR-17~92 expression in mouse embryos. J.A. and A.V. designed and supervised the project and wrote the manuscript. A.M., M.V., S.L., L.d.P., E.Y. and A.H.-C. provided critical input into project development and manuscript preparation. All other coauthors identified subjects with Feingold syndrome and performed related clinical and laboratory studies (L.F., V.D., A.V.H., D.G., A.G. and S.M.). Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Jeanne Amiel or * Andrea Ventura Author Details * Loïc de Pontual Search for this author in: * NPG journals * PubMed * Google Scholar * Evelyn Yao Search for this author in: * NPG journals * PubMed * Google Scholar * Patrick Callier Search for this author in: * NPG journals * PubMed * Google Scholar * Laurence Faivre Search for this author in: * NPG journals * PubMed * Google Scholar * Valérie Drouin Search for this author in: * NPG journals * PubMed * Google Scholar * Sandra Cariou Search for this author in: * NPG journals * PubMed * Google Scholar * Arie Van Haeringen Search for this author in: * NPG journals * PubMed * Google Scholar * David Geneviève Search for this author in: * NPG journals * PubMed * Google Scholar * Alice Goldenberg Search for this author in: * NPG journals * PubMed * Google Scholar * Myriam Oufadem Search for this author in: * NPG journals * PubMed * Google Scholar * Sylvie Manouvrier Search for this author in: * NPG journals * PubMed * Google Scholar * Arnold Munnich Search for this author in: * NPG journals * PubMed * Google Scholar * Joana Alves Vidigal Search for this author in: * NPG journals * PubMed * Google Scholar * Michel Vekemans Search for this author in: * NPG journals * PubMed * Google Scholar * Stanislas Lyonnet Search for this author in: * NPG journals * PubMed * Google Scholar * Alexandra Henrion-Caude Search for this author in: * NPG journals * PubMed * Google Scholar * Andrea Ventura Contact Andrea Ventura Search for this author in: * NPG journals * PubMed * Google Scholar * Jeanne Amiel Contact Jeanne Amiel Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (2M) Supplementary Figures 1–6, Supplementary Tables 1–3 and Supplementary Note. Additional data
• Bayesian inference of ancient human demography from individual genome sequences
  - Nat Genet 43(10):1031-1034 (2011)
  Nature Genetics | Letter Bayesian inference of ancient human demography from individual genome sequences * Ilan Gronau1 * Melissa J Hubisz1 * Brad Gulko2 * Charles G Danko1 * Adam Siepel1 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:1031–1034Year published:(2011)DOI:doi:10.1038/ng.937Received22 February 2011Accepted16 August 2011Published online18 September 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Whole-genome sequences provide a rich source of information about human evolution. Here we describe an effort to estimate key evolutionary parameters based on the whole-genome sequences of six individuals from diverse human populations. We used a Bayesian, coalescent-based approach to obtain information about ancestral population sizes, divergence times and migration rates from inferred genealogies at many neutrally evolving loci across the genome. We introduce new methods for accommodating gene flow between populations and integrating over possible phasings of diploid genotypes. We also describe a custom pipeline for genotype inference to mitigate biases from heterogeneous sequencing technologies and coverage levels. Our analysis indicates that the San population of southern Africa diverged from other human populations approximately 108–157 thousand years ago, that Eurasians diverged from an ancestral African population 38–64 thousand years ago, and that the effective p! opulation size of the ancestors of all modern humans was ~9,000. View full text Figures at a glance * Figure 1: Population phylogeny and genealogies. The population phylogeny assumed in this study with one diploid genome per population (Table 1) and a haploid chimpanzee outgroup. We included the Yoruban and Bantu individuals in the analysis as alternative African ingroups (denoted X) because their relationship to one another was uncertain (Supplementary Note). The free parameters in our model include the five population divergence times (τ) and the ten effective population sizes (θ), all expressed in units of expected mutations per site. We also considered various 'migration bands' (gray double-headed arrow) to allow for gene flow between populations, treating the (constant) migration rates along bands as free parameters. The two parameters of primary interest were the San (τKHEXS) and African-Eurasian (τKHEX) divergence times (div.). We obtained absolute divergence times (in years) and effective population sizes (in numbers of individuals) by assuming a human-chimpanzee average genomic divergence time of 5.6–7.6 My! a and a point estimate of 6.5 Mya. * Figure 2: Results of the simulation study. Simulations assumed a population tree like the one shown in Figure 1 and plausible divergence times, population sizes and migration scenarios (Supplementary Note). () Accuracy of estimated African-Eurasian (τKHEX) and San (τKHEXS) divergence times without migration. Dotted lines indicate the values assumed for the simulations, and each boxplot summarizes the posterior mean estimates in six separate runs of G-PhoCS. Results are shown for correctly phased data (gold) and integration over unknown phasings (red). A random phasing procedure produced substantially poorer results (Supplementary Fig. 10). Most estimates fall within 10% of the true value, except for the smallest assumed divergence times, where weak information in the data leads to an upward bias. () Accuracy of the estimated San divergence time (τKHEXS) and the Yoruban-Bantu population size (θX) in simulations with four levels of constant-rate migration (denoted 0, 1, 2 and 3 in order of increasing strength) from! population S to population X. Ratios of the estimated to true values are shown when migration is not allowed (blue) and is allowed (red) in the model. Each boxplot summarizes 12 runs. Notice that there is a pronounced bias when migration is present but is not modeled, but this bias is eliminated when migration is added to the model. Simulated and estimated migration rates (measured in expected number of migrants per generation) are shown at right (see Supplementary Figs. 9–11 for the complete results). * Figure 3: Parameter estimates from real data. Estimates of population divergence times (), migration rates () and effective population sizes () obtained for various scenarios. In and , both mutation-scaled (left) and calibrated (right) y axes are shown (with a calibration of Tdiv = 6.5 Mya). Results are shown for scenarios with either the Yoruban or Bantu ingroup X and with or without a migration band between X and the San ingroup. Panel shows estimated migration rates for 14 different migration bands. Only the Yoruban-San (Y-S) and Bantu-San (B-S) migration scenarios are strongly supported. In all panels, each bar represents the mean estimate and 95% credible interval (error bars) of a single representative run of the program (see Supplementary Tables 4 and 5 and Supplementary Figs. 12 and 13 for complete results). Author information * Author information * Supplementary information Affiliations * Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, USA. * Ilan Gronau, * Melissa J Hubisz, * Charles G Danko & * Adam Siepel * Graduate Field of Computer Science, Cornell University, Ithaca, New York, USA. * Brad Gulko Contributions A.S. conceived of and designed the study. I.G. implemented G-PhoCS and applied it to both simulated and real data. B.G. implemented BSNP and applied it to the individual genomes. I.G., M.J.H., B.G., C.G.D. and A.S. performed additional statistical analyses. I.G. and A.S. wrote the paper with review and contributions by all authors. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Adam Siepel Author Details * Ilan Gronau Search for this author in: * NPG journals * PubMed * Google Scholar * Melissa J Hubisz Search for this author in: * NPG journals * PubMed * Google Scholar * Brad Gulko Search for this author in: * NPG journals * PubMed * Google Scholar * Charles G Danko Search for this author in: * NPG journals * PubMed * Google Scholar * Adam Siepel Contact Adam Siepel Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (4M) Supplementary Figures 1–13, Supplementary Tables 1–7 and Supplementary Note. Additional data
• The genome of the mesopolyploid crop species Brassica rapa
  - Nat Genet 43(10):1035-1039 (2011)
  Nature Genetics | Letter The genome of the mesopolyploid crop species Brassica rapa * The Brassica rapa Genome Sequencing Project Consortium * Xiaowu Wang1 * Hanzhong Wang2 * Jun Wang3, 4 * Rifei Sun1 * Jian Wu1 * Shengyi Liu2 * Yinqi Bai3 * Jeong-Hwan Mun5 * Ian Bancroft6 * Feng Cheng1 * Sanwen Huang1 * Xixiang Li1 * Wei Hua2 * Junyi Wang3 * Xiyin Wang7, 8, 9 * Michael Freeling10 * J Chris Pires11 * Andrew H Paterson9 * Boulos Chalhoub12 * Bo Wang3 * Alice Hayward13, 14 * Andrew G Sharpe15 * Beom-Seok Park5 * Bernd Weisshaar16 * Binghang Liu3 * Bo Li3 * Bo Liu1 * Chaobo Tong2 * Chi Song3 * Christopher Duran13, 17 * Chunfang Peng3 * Chunyu Geng3 * Chushin Koh15 * Chuyu Lin3 * David Edwards13, 17 * Desheng Mu3 * Di Shen1 * Eleni Soumpourou6 * Fei Li1 * Fiona Fraser6 * Gavin Conant18 * Gilles Lassalle19 * Graham J King20 * Guusje Bonnema21 * Haibao Tang10 * Haiping Wang1 * Harry Belcram12 * Heling Zhou3 * Hideki Hirakawa22 * Hiroshi Abe23 * Hui Guo9 * Hui Wang1 * Huizhe Jin9 * Isobel A P Parkin24 * Jacqueline Batley13, 14 * Jeong-Sun Kim5 * Jérémy Just12 * Jianwen Li3 * Jiaohui Xu3 * Jie Deng1 * Jin A Kim5 * Jingping Li9 * Jingyin Yu2 * Jinling Meng25 * Jinpeng Wang7, 8 * Jiumeng Min3 * Julie Poulain26 * Jun Wang20 * Katsunori Hatakeyama27 * Kui Wu3 * Li Wang7, 8 * Lu Fang1 * Martin Trick6 * Matthew G Links24 * Meixia Zhao2 * Mina Jin5 * Nirala Ramchiary28 * Nizar Drou6 * Paul J Berkman13, 17 * Qingle Cai3 * Quanfei Huang3 * Ruiqiang Li3 * Satoshi Tabata22 * Shifeng Cheng3 * Shu Zhang3 * Shujiang Zhang1 * Shunmou Huang2 * Shusei Sato22 * Silong Sun1 * Soo-Jin Kwon5 * Su-Ryun Choi28 * Tae-Ho Lee9 * Wei Fan3 * Xiang Zhao3 * Xu Tan9 * Xun Xu3 * Yan Wang1 * Yang Qiu1 * Ye Yin3 * Yingrui Li3 * Yongchen Du1 * Yongcui Liao1 * Yongpyo Lim28 * Yoshihiro Narusaka29 * Yupeng Wang8 * Zhenyi Wang7, 8 * Zhenyu Li3 * Zhiwen Wang3 * Zhiyong Xiong11 * Zhonghua Zhang1 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:1035–1039Year published:(2011)DOI:doi:10.1038/ng.919Received07 March 2011Accepted03 August 2011Published online28 August 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg We report the annotation and analysis of the draft genome sequence of Brassica rapa accession Chiifu-401-42, a Chinese cabbage. We modeled 41,174 protein coding genes in the B. rapa genome, which has undergone genome triplication. We used Arabidopsis thaliana as an outgroup for investigating the consequences of genome triplication, such as structural and functional evolution. The extent of gene loss (fractionation) among triplicated genome segments varies, with one of the three copies consistently retaining a disproportionately large fraction of the genes expected to have been present in its ancestor. Variation in the number of members of gene families present in the genome may contribute to the remarkable morphological plasticity of Brassica species. The B. rapa genome sequence provides an important resource for studying the evolution of polyploid genomes and underpins the genetic improvement of Brassica oil and vegetable crops. View full text Figures at a glance * Figure 1: Chromosomal distribution of the main B. rapa genome features. Area charts quantify retrotransposons, genes (exons and introns) and DNA transposons. The x axis denotes the physical position along the B. rapa chromosomes in units of million (M) bases. * Figure 2: Venn diagram showing unique and shared gene families between and among four sequenced dicotyledonous species (B. rapa, A. thaliana, C. papaya and V. vinifera). * Figure 3: Segmental collinearity of the genomes of B. rapa and A. thaliana. Conserved collinear blocks of gene models are shown between the ten chromosomes of the B. rapa genome (horizontal axis) and the five chromosomes of the A. thaliana genome (vertical axis). These blocks are labeled A to X and are color coded by inferred ancestral chromosome following established convention. * Figure 4: The density of orthologous genes in three subgenomes (LF, MF1 and MF2) of B. rapa compared to A. thaliana. The x axis denotes the physical position of each A. thaliana gene locus. The y axis denotes the percentage of retained orthologous genes in B. rapa subgenomes around each A. thaliana gene, where 500 genes flanking each side of a certain gene locus were analyzed, giving a total window size of 1,001 genes. * Figure 5: The over retention genes in B. rapa showing strong bias. The x axis denotes the gene category. The y axis denotes the ratio of different copies in each category. The number of B. rapa orthologs of each class is indicated above each bar. RE, response to environment; RH, response to hormone; TF, transcription factor; CR, cytosolic ribosome; CW, cell wall. () The orange bar is the ratio of one- or two-copy orthologs, and the light green bar is the ratio of three copies. () The yellow bar is the ratio of one-copy orthologs, and the dark green bar is the ratio of two- or three-copy orthologs. The last category is the total sets of all orthologs listed as a control. The P value of each category is indicated under the bars. GO, Gene Ontology. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions DNA Data Bank of Japan * AENI00000000 * AENI01000000 Author information * Accession codes * Author information * Supplementary information Affiliations * Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences (IVF, CAAS), Beijing, China. * Xiaowu Wang, * Rifei Sun, * Jian Wu, * Feng Cheng, * Sanwen Huang, * Xixiang Li, * Bo Liu, * Di Shen, * Fei Li, * Haiping Wang, * Hui Wang, * Jie Deng, * Lu Fang, * Shujiang Zhang, * Silong Sun, * Yan Wang, * Yang Qiu, * Yongchen Du, * Yongcui Liao & * Zhonghua Zhang * Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, Wuhan, Hubei, China. * Hanzhong Wang, * Shengyi Liu, * Wei Hua, * Chaobo Tong, * Jingyin Yu, * Meixia Zhao & * Shunmou Huang * BGI-Shenzhen, Shenzhen, China. * Jun Wang, * Yinqi Bai, * Junyi Wang, * Bo Wang, * Binghang Liu, * Bo Li, * Chi Song, * Chunfang Peng, * Chunyu Geng, * Chuyu Lin, * Desheng Mu, * Heling Zhou, * Jianwen Li, * Jiaohui Xu, * Jiumeng Min, * Kui Wu, * Qingle Cai, * Quanfei Huang, * Ruiqiang Li, * Shifeng Cheng, * Shu Zhang, * Wei Fan, * Xiang Zhao, * Xun Xu, * Ye Yin, * Yingrui Li, * Zhenyu Li & * Zhiwen Wang * Department of Biology, University of Copenhagen, Copenhagen, Denmark. * Jun Wang * Department of Agricultural Biotechnology, National Academy of Agricultural Science, Rural Development Administration, Suwon, Korea. * Jeong-Hwan Mun, * Beom-Seok Park, * Jeong-Sun Kim, * Jin A Kim, * Mina Jin & * Soo-Jin Kwon * John Innes Centre, Norwich Research Park, Colney, Norwich, UK. * Ian Bancroft, * Eleni Soumpourou, * Fiona Fraser, * Martin Trick & * Nizar Drou * Center for Genomics and Computational Biology, School of Life Sciences, Hebei United University, Tangshan, Hebei, China. * Xiyin Wang, * Jinpeng Wang, * Li Wang & * Zhenyi Wang * School of Sciences, Hebei United University, Tangshan, Hebei, China. * Xiyin Wang, * Jinpeng Wang, * Li Wang, * Yupeng Wang & * Zhenyi Wang * Plant Genome Mapping Laboratory, University of Georgia, Athens, Georgia, USA. * Xiyin Wang, * Andrew H Paterson, * Hui Guo, * Huizhe Jin, * Jingping Li, * Tae-Ho Lee & * Xu Tan * Department of Plant and Microbial Biology, University of California, Berkeley, California, USA. * Michael Freeling & * Haibao Tang * Division of Biological Sciences, Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA. * J Chris Pires & * Zhiyong Xiong * Organization and Evolution of Plant Genomes, Unité de Recherche en Génomique Végétale, Unité Mixte de Recherché 1165, (Inland Northwest Research Alliance-Centre National de la Recherche Scientifique, Université Evry Val d'Essonne), Evry, France. * Boulos Chalhoub, * Harry Belcram & * Jérémy Just * University of Queensland, School of Agriculture and Food Sciences, Brisbane, Queensland, Australia. * Alice Hayward, * Christopher Duran, * David Edwards, * Jacqueline Batley & * Paul J Berkman * Australian Research Council Centre of Excellence for Integrative Legume Research, Brisbane, Queensland, Australia. * Alice Hayward & * Jacqueline Batley * National Research Council-Plant Biotechnology Institute, Saskatoon, Saskatchewan, Canada. * Andrew G Sharpe & * Chushin Koh * Center for Biotechnology, Bielefeld University, Bielefeld, Germany. * Bernd Weisshaar * Australian Centre for Plant Functional Genomics, Brisbane, Queensland, Australia. * Christopher Duran, * David Edwards & * Paul J Berkman * Division of Animal Sciences, University of Missouri, Columbia, Missouri, USA. * Gavin Conant * Inland Northwest Research Alliance-Agrocampus Rennes–University of Rennes 1, Unité Mixte de Recherché 118 Amélioration des Plantes et Biotechnologies Végétales, Le Rheu Cedex, France. * Gilles Lassalle * Centre for Crop Genetic Improvement, Rothamsted Research, West Common, Harpenden, UK. * Graham J King & * Jun Wang * Droevendaalsesteeg 1, Wageningen University, Wageningen, The Netherlands. * Guusje Bonnema * Kazusa DNA Research Institute, 2-6-7 Kazusa-Kamatari, Kisarazu, Chiba, Japan. * Hideki Hirakawa, * Satoshi Tabata & * Shusei Sato * Experimental Plant Division, RIKEN BioResource Center, Tsukuba, Japan. * Hiroshi Abe * Agriculture and Agri-Food Canada, Saskatoon, Saskatchewan, Canada. * Isobel A P Parkin & * Matthew G Links * National Key Laboratory of Crop Genetic Improvement, Huazhong Agricultural University, Wuhan, China. * Jinling Meng * Genoscope, Institut de Génomique du Commissariat à l'Energie Atomique, 2 rue Gaston Crémieux, Evry, France. * Julie Poulain * National Institute of Vegetable and Tea Science, Tsu, Japan. * Katsunori Hatakeyama * Molecular Genetics and Genomics Lab, Department of Horticulture, Chungnam National University, Daejeon, Republic of Korea. * Nirala Ramchiary, * Su-Ryun Choi & * Yongpyo Lim * Research Institute for Biological Sciences, Okayama, Japan. * Yoshihiro Narusaka Consortia * The Brassica rapa Genome Sequencing Project Consortium Contributions Xiaowu Wang, J. Wu, S.L., Y.B., J.-H.M. and I.B. Bo Wang (group leader), Xiaowu Wang (group leader), B.C. (group leader), Jun Wang (BGI), K.W., J. Wu, S.L., W.H., B.-S.P., I.B., D.E., I.A.P.P., J.-H.M., H.A., Bernd Weisshaar, Shusei Sato, H.H., S.T., A.G.S., Y. Lim, G.B., J.B., C.L., C.G., J.P., S.-J.K., J.A.K., M.T., F.F., E.S., M.G.L., C.K., K.H., Y.N., P.J.B. and C.D. Junyi Wang (group leader), Jun Wang (BGI), D.M., Y. Li, X.X., Bo Liu, Silong Sun, Z.Z., Z.L., Binghang Liu, Q.C., Shu Zhang, Y.B., Zhiwen Wang, X.Z., C.S., J.Y. and J.J. J. Wu (group leader), W.H. (group leader), G.J.K., Y. Lim, B.-S.P., I.B., J.B., D.E., Yan Wang, Bo Liu, Silong Sun, Jun Wang (Rothamsted), I.A.P.P., J. Meng, Hui Wang, J.D., Y. Liao, Y.B., Haiping Wang, M.J., J.-S.K., S.-R.C., N.R. and A.H. Y.B. (group leader), S.L. (group leader), R.L., W.F., Q.H., F.C., Bo Liu, D.E., J. Min, Jianwen Li, C.P., H.Z., Shunmou Huang, B.C., J.J., H.B., G.L., N.D. and M.T. F.C. (group leader), Sanwen Huang ! (group leader), Y.B., Xiaowu Wang, B. Li, S.C., Y.Y., J.X. and C.T. Xiaowu Wang (group leader), J.C.P. (group leader), Xiyin Wang (group leader), I.B., F.C., H.T., G.C., H.G., T.-H.L., Jinpeng Wang and Zhenyi Wang. M.F. (group leader), A.H.P. (group leader), F.C., H.T., Bo Liu, Silong Sun, L.F., Z.X., M.Z., Jingping Li, H.J. and X.T. J. Wu (group leader), X.L. (group leader), R.S., Hanzhong Wang, Y.D., Xiaowu Wang, Hui Wang, J.D., D.S., Y.Q., Shujiang Zhang, F.L., L.W. and Yupeng Wang. Xiaowu Wang1, Hanzhong Wang2, Jun Wang3,4, Rifei Sun1, Jian Wu1, Shengyi Liu2, Yinqi Bai3, Jeong-Hwan Mun5, Ian Bancroft6, Feng Cheng1, Sanwen Huang1, Xixiang Li1, Wei Hua2, Junyi Wang3, Xiyin Wang7,9, Michael Freeling10, J Chris Pires11, Andrew H Paterson9, Boulos Chalhoub12, Bo Wang3, Alice Hayward13,14, Andrew G Sharpe15, Beom-Seok Park5, Bernd Weisshaar16, Binghang Liu3, Bo Li3, Bo Liu1, Chaobo Tong2, Chi Song3, Christopher Duran13,17, Chunfang Peng3, Chunyu Geng3, Chushin Koh15, Chuyu Lin3, David Edwards13,17, Desheng Mu3, Di Shen1, Eleni Soumpourou6, Fei Li1, Fiona Fraser6, Gavin Conant18, Gilles Lassalle19, Graham J King20, Guusje Bonnema21, Haibao Tang10, Haiping Wang1, Harry Belcram12, Heling Zhou3, Hideki Hirakawa22, Hiroshi Abe23, Hui Guo9, Hui Wang1, Huizhe Jin9, Isobel A P Parkin24, Jacqueline Batley13,14, Jeong-Sun Kim5, Jérémy Just12, Jianwen Li3, Jiaohui Xu3, Jie Deng1, Jin A Kim5, Jingping Li9, Jingyin Yu2, Jinling Meng25, Jinpeng Wang7,8, Jiumeng Min3, Ju! lie Poulain26, Jun Wang20, Katsunori Hatakeyama27, Kui Wu3, Li Wang7,8, Lu Fang1, Martin Trick6, Matthew G Links24, Meixia Zhao2, Mina Jin5, Nirala Ramchiary28, Nizar Drou6, Paul J Berkman13,17, Qingle Cai3, Quanfei Huang3, Ruiqiang Li3, Satoshi Tabata22, Shifeng Cheng3, Shu Zhang3, Shujiang Zhang1, Shunmou Huang2, Shusei Sato22, Silong Sun1, Soo-Jin Kwon5, Su-Ryun Choi28, Tae-Ho Lee9, Wei Fan3, Xiang Zhao3, Xu Tan9, Xun Xu3, Yan Wang1, Yang Qiu1, Ye Yin3, Yingrui Li3, Yongchen Du1, Yongcui Liao1, Yongpyo Lim28, Yoshihiro Narusaka29, Yupeng Wang8, Zhenyi Wang7,8, Zhenyu Li3, Zhiwen Wang3, Zhiyong Xiong11 & Zhonghua Zhang1 Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Xiaowu Wang or * Jun Wang or * Hanzhong Wang or * Rifei Sun Author Details * The Brassica rapa Genome Sequencing Project Consortium * Xiaowu Wang Contact Xiaowu Wang Search for this author in: * NPG journals * PubMed * Google Scholar * Hanzhong Wang Contact Hanzhong Wang Search for this author in: * NPG journals * PubMed * Google Scholar * Jun Wang Search for this author in: * NPG journals * PubMed * Google Scholar * Rifei Sun Contact Rifei Sun Search for this author in: * NPG journals * PubMed * Google Scholar * Jian Wu Search for this author in: * NPG journals * PubMed * Google Scholar * Shengyi Liu Search for this author in: * NPG journals * PubMed * Google Scholar * Yinqi Bai Search for this author in: * NPG journals * PubMed * Google Scholar * Jeong-Hwan Mun Search for this author in: * NPG journals * PubMed * Google Scholar * Ian Bancroft Search for this author in: * NPG journals * PubMed * Google Scholar * Feng Cheng Search for this 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Search for this author in: * NPG journals * PubMed * Google Scholar * Zhiwen Wang Search for this author in: * NPG journals * PubMed * Google Scholar * Zhiyong Xiong Search for this author in: * NPG journals * PubMed * Google Scholar * Zhonghua Zhang 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 Tables 1–21 and Supplementary Figures 1–25. 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• Erratum: Common variants in P2RY11 are associated with narcolepsy
  - Nat Genet 43(10):1040 (2011)
  Nature Genetics | Erratum Erratum: Common variants in P2RY11 are associated with narcolepsy * Birgitte R Kornum * Minae Kawashima * Juliette Faraco * Ling Lin * Thomas J Rico * Stephanie Hesselson * Robert C Axtell * Hedwich Kuipers * Karin Weiner * Alexandra Hamacher * Matthias U Kassack * Fang Han * Stine Knudsen * Jing Li * Xiaosong Dong * Juliane Winkelmann * Giuseppe Plazzi * Sona Nevsimalova * Seung-Chul Hong * Yutaka Honda * Makoto Honda * Birgit Högl * Thanh G N Ton * Jacques Montplaisir * Patrice Bourgin * David Kemlink * Yu-Shu Huang * Simon Warby * Mali Einen * Jasmin L Eshragh * Taku Miyagawa * Alex Desautels * Elisabeth Ruppert * Per Egil Hesla * Francesca Poli * Fabio Pizza * Birgit Frauscher * Jong-Hyun Jeong * Sung-Pil Lee * Kingman P Strohl * William T Longstreth Jr * Mark Kvale * Marie Dobrovolna * Maurice M Ohayon * Gerald T Nepom * H-Erich Wichmann * Guy A Rouleau * Christian Gieger * Douglas F Levinson * Pablo V Gejman * Thomas Meitinger * Paul Peppard * Terry Young * Poul Jennum * Lawrence Steinman * Katsushi Tokunaga * Pui-Yan Kwok * Neil Risch * Joachim Hallmayer * Emmanuel MignotJournal name:Nature GeneticsVolume: 43,Page:1040Year published:(2011)DOI:doi:10.1038/ng1011-1040bPublished online28 September 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, 66–71 (2011); published online 19 December 2010; corrected after print 22 September 2011 In the version of this article initially published, the percentage reduction of P2RY11 expression in CD8+ T lymphocytes was incorrectly given as 339%, when it should have been 72%. The percentage was not given for NK cells and should have been 70%. The errors have been corrected in the HTML and PDF versions of the article. Additional data Author Details * Birgitte R Kornum Search for this author in: * NPG journals * PubMed * Google Scholar * Minae Kawashima Search for this author in: * NPG journals * PubMed * Google Scholar * Juliette Faraco Search for this author in: * NPG journals * PubMed * Google Scholar * Ling Lin Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas J Rico Search for this author in: * NPG journals * PubMed * Google Scholar * Stephanie Hesselson Search for this author in: * NPG journals * PubMed * Google Scholar * Robert C Axtell Search for this author in: * NPG journals * PubMed * Google Scholar * Hedwich Kuipers Search for this author in: * NPG journals * PubMed * Google Scholar * Karin Weiner Search for this author in: * NPG journals * PubMed * Google Scholar * Alexandra Hamacher Search for this author in: * NPG journals * PubMed * Google Scholar * Matthias U Kassack Search for this author in: * NPG journals * PubMed * Google Scholar * Fang Han Search for 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• Corrigendum: Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes
  - Nat Genet 43(10):1040 (2011)
  Nature Genetics | Corrigendum Corrigendum: Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes * Kerrin S Small * Åsa K Hedman * Elin Grundberg * Alexandra C Nica * Gudmar Thorleifsson * Augustine Kong * Unnur Thorsteindottir * So-Youn Shin * Hannah B Richards * Nicole Soranzo * Kourosh R Ahmadi * Cecilia M Lindgren * Kari Stefansson * Emmanouil T Dermitzakis * Panos Deloukas * Timothy D Spector * Mark I McCarthyJournal name:Nature GeneticsVolume: 43,Page:1040Year published:(2011)DOI:doi:10.1038/ng1011-1040cPublished online28 September 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, 561–564 (2011); published online 15 May 2011; corrected after print 22 September 2011 In the version of this article initially published, there were several errors in the P values reported in the Adiponectin and HOMA-IR columns of Table 3. These errors have been corrected in the HTML and PDF versions of the article. Additional data Author Details * Kerrin S Small Search for this author in: * NPG journals * PubMed * Google Scholar * Åsa K Hedman Search for this author in: * NPG journals * PubMed * Google Scholar * Elin Grundberg Search for this author in: * NPG journals * PubMed * Google Scholar * Alexandra C Nica Search for this author in: * NPG journals * PubMed * Google Scholar * Gudmar Thorleifsson Search for this author in: * NPG journals * PubMed * Google Scholar * Augustine Kong Search for this author in: * NPG journals * PubMed * Google Scholar * Unnur Thorsteindottir Search for this author in: * NPG journals * PubMed * Google Scholar * So-Youn Shin Search for this author in: * NPG journals * PubMed * Google Scholar * Hannah B Richards Search for this author in: * NPG journals * PubMed * Google Scholar * Nicole Soranzo Search for this author in: * NPG journals * PubMed * Google Scholar * Kourosh R Ahmadi Search for this author in: * NPG journals * PubMed * Google Scholar * Cecilia M Lindgren Search for this author in: * NPG journals * PubMed * Google Scholar * Kari Stefansson Search for this author in: * NPG journals * PubMed * Google Scholar * Emmanouil T Dermitzakis Search for this author in: * NPG journals * PubMed * Google Scholar * Panos Deloukas Search for this author in: * NPG journals * PubMed * Google Scholar * Timothy D Spector Search for this author in: * NPG journals * PubMed * Google Scholar * Mark I McCarthy Search for this author in: * NPG journals * PubMed * Google Scholar
• Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2
  - Nat Genet 43(10):1040 (2011)
  Nature Genetics | Corrigendum Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2 * Thorsten Thye * Fredrik O Vannberg * Sunny H Wong * Ellis Owusu-Dabo * Ivy Osei * John Gyapong * Giorgio Sirugo * Fatou Sisay-Joof * Anthony Enimil * Margaret A Chinbuah * Sian Floyd * David K Warndorff * Lifted Sichali * Simon Malema * Amelia C Crampin * Bagrey Ngwira * Yik Y Teo * Kerrin Small * Kirk Rockett * Dominic Kwiatkowski * Paul E Fine * Philip C Hill * Melanie Newport * Christian Lienhardt * Richard A Adegbola * Tumani Corrah * Andreas Ziegler * Andrew P Morris * Christian G Meyer * Rolf D Horstmann * Adrian V S HillJournal name:Nature GeneticsVolume: 43,Page:1040Year published:(2011)DOI:doi:10.1038/ng1011-1040aPublished online28 September 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, 739–741 (2010); published online 8 August 2010; corrected after print 22 September 2011 In the version of this article initially published, an acknowledgment was missing. The study was supported by funding from the NIHR Oxford Biomedical Research Centre programme. The error has been corrected in the HTML and PDF versions of the article. Additional data Author Details * Thorsten Thye Search for this author in: * NPG journals * PubMed * Google Scholar * Fredrik O Vannberg Search for this author in: * NPG journals * PubMed * Google Scholar * Sunny H Wong Search for this author in: * NPG journals * PubMed * Google Scholar * Ellis Owusu-Dabo Search for this author in: * NPG journals * PubMed * Google Scholar * Ivy Osei Search for this author in: * NPG journals * PubMed * Google Scholar * John Gyapong Search for this author in: * NPG journals * PubMed * Google Scholar * Giorgio Sirugo Search for this author in: * NPG journals * PubMed * Google Scholar * Fatou Sisay-Joof Search for this author in: * NPG journals * PubMed * Google Scholar * Anthony Enimil Search for this author in: * NPG journals * PubMed * Google Scholar * Margaret A Chinbuah Search for this author in: * NPG journals * PubMed * Google Scholar * Sian Floyd Search for this author in: * NPG journals * PubMed * Google Scholar * David K Warndorff Search for this author in: * NPG journals * PubMed * Google Scholar * Lifted Sichali Search for this author in: * NPG journals * PubMed * Google Scholar * Simon Malema Search for this author in: * NPG journals * PubMed * Google Scholar * Amelia C Crampin Search for this author in: * NPG journals * PubMed * Google Scholar * Bagrey Ngwira Search for this author in: * NPG journals * PubMed * Google Scholar * Yik Y Teo Search for this author in: * NPG journals * PubMed * Google Scholar * Kerrin Small Search for this author in: * NPG journals * PubMed * Google Scholar * Kirk Rockett Search for this author in: * NPG journals * PubMed * Google Scholar * Dominic Kwiatkowski Search for this author in: * NPG journals * PubMed * Google Scholar * Paul E Fine Search for this author in: * NPG journals * PubMed * Google Scholar * Philip C Hill Search for this author in: * NPG journals * PubMed * Google Scholar * Melanie Newport Search for this author in: * NPG journals * PubMed * Google Scholar * Christian Lienhardt Search for this author in: * NPG journals * PubMed * Google Scholar * Richard A Adegbola Search for this author in: * NPG journals * PubMed * Google Scholar * Tumani Corrah Search for this author in: * NPG journals * PubMed * Google Scholar * Andreas Ziegler Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew P Morris Search for this author in: * NPG journals * PubMed * Google Scholar * Christian G Meyer Search for this author in: * NPG journals * PubMed * Google Scholar * Rolf D Horstmann Search for this author in: * NPG journals * PubMed * Google Scholar * Adrian V S Hill Search for this author in: * NPG journals * PubMed * Google Scholar