Article | Published:

Genome-wide association study identifies eight loci associated with blood pressure

Nature Genetics volume 41, pages 666676 (2009) | Download Citation

Abstract

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10−24), CYP1A2 (P = 1 × 10−23), FGF5 (P = 1 × 10−21), SH2B3 (P = 3 × 10−18), MTHFR (P = 2 × 10−13), c10orf107 (P = 1 × 10−9), ZNF652 (P = 5 × 10−9) and PLCD3 (P = 1 × 10−8) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

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References

  1. 1.

    , , , & Selected major risk factors and global and regional burden of disease. Lancet 360, 1347–1360 (2002).

  2. 2.

    , , , & Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 360, 1903–1913 (2002).

  3. 3.

    The World Health Organization. The World Health Report 2002–Reducing Risks, Promoting Healthy Life (World Health Organization, 2002).

  4. 4.

    et al. Primary prevention of hypertension: clinical and public health advisory from The National High Blood Pressure Education Program. J. Am. Med. Assoc. 288, 1882–1888 (2002).

  5. 5.

    et al. Blood pressure aggregation in families. Am. J. Epidemiol. 110, 304–312 (1979).

  6. 6.

    , & Molecular mechanisms of human hypertension. Cell 104, 545–556 (2001).

  7. 7.

    et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat. Genet. 40, 592–599 (2008).

  8. 8.

    et al. Haplotypes of the WNK1 gene associate with blood pressure variation in a severely hypertensive population from the British Genetics of Hypertension study. Hum. Mol. Genet. 14, 1805–1814 (2005).

  9. 9.

    et al. Association of WNK1 gene polymorphisms and haplotypes with ambulatory blood pressure in the general population. Circulation 112, 3423–3429 (2005).

  10. 10.

    et al. Common variants in genes underlying monogenic hypertension and hypotension and blood pressure in the general population. Hypertension 51, 1658–1664 (2008).

  11. 11.

    The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  12. 12.

    et al. Framingham Heart Study 100K Project: genome-wide associations for blood pressure and arterial stiffness. BMC Med.Genet 8(Suppl. 1), S3 (2007).

  13. 13.

    , , & Adjusting for treatment effects in studies of quantitative traits: antihypertensive therapy and systolic blood pressure. Stat. Med. 24, 2911–2935 (2005).

  14. 14.

    & Genomic control for association studies. Biometrics 55, 997–1004 (1999).

  15. 15.

    , , & Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet. Epidemiol. 32, 381–385 (2008).

  16. 16.

    et al. Genome-wide association study of blood pressure and hypertension. Nat. Genet. advance online publication, doi:10.1038/ng.384 (10 May 2009).

  17. 17.

    et al. P450c17 deficiency in Brazilian patients: biochemical diagnosis through progesterone levels confirmed by CYP17 genotyping. J. Clin. Endocrinol. Metab. 88, 5739–5746 (2003).

  18. 18.

    , , & The genetic and functional basis of isolated 17,20-lyase deficiency. Nat. Genet. 17, 201–205 (1997).

  19. 19.

    et al. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am. J. Hum. Genet. 58, 35–41 (1996).

  20. 20.

    et al. Methylenetetrahydrofolate reductase polymorphism and pre-eclampsia. J. Med. Genet. 34, 525–526 (1997).

  21. 21.

    , , , & A meta-analysis of association between C677T polymorphism in the methylenetetrahydrofolate reductase gene and hypertension. Eur. J. Hum. Genet. 15, 1239–1245 (2007).

  22. 22.

    et al. Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension. Science 267, 679–681 (1995).

  23. 23.

    et al. Association of common variants in NPPA and NPPB with circulating natriuretic peptides and blood pressure. Nat. Genet. 41, 348–353 (2009).

  24. 24.

    et al. Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK. Nat. Genet. 14, 152–156 (1996).

  25. 25.

    et al. Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat. Genet. 12, 24–30 (1996).

  26. 26.

    et al. Cloning and characterization of ATRAP, a novel protein that interacts with the angiotensin II type 1 receptor. J. Biol. Chem. 274, 17058–17062 (1999).

  27. 27.

    et al. Multiple roles of phosphoinositide-specific phospholipase C isozymes. BMB Rep. 41, 415–434 (2008).

  28. 28.

    & The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nat. Rev. Cancer 6, 947–960 (2006).

  29. 29.

    , , & Functional significance of a C → A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Br. J. Clin. Pharmacol. 27, 445–449 (1999).

  30. 30.

    et al. Microarray analysis of PDGFR alpha+ populations in ES cell differentiation culture identifies genes involved in differentiation of mesoderm and mesenchyme including ARID3b that is essential for development of embryonic mesenchymal cells. Dev. Biol. 293, 25–37 (2006).

  31. 31.

    FGF induces hypertrophy and angiogenesis in hibernating myocardium. Circ. Res. 96, 705–707 (2005).

  32. 32.

    et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat. Genet. 39, 857–864 (2007).

  33. 33.

    et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat. Genet. 40, 395–402 (2008).

  34. 34.

    et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat. Genet. 41, 342–347 (2009).

  35. 35.

    , , , & The adaptor molecule Lnk negatively regulates tumor necrosis factor-alpha-dependent VCAM-1 expression in endothelial cells through inhibition of the ERK1 and -2 pathways. J. Biol. Chem. 281, 20148–20159 (2006).

  36. 36.

    et al. Cytokine signaling and hematopoietic homeostasis are disrupted in Lnk-deficient mice. J. Exp. Med. 195, 1599–1611 (2002).

  37. 37.

    , , & A map of recent positive selection in the human genome. PLoS Biol. 4, e72 (2006).

  38. 38.

    , , , & Endothelium-specific GTP cyclohydrolase I overexpression attenuates blood pressure progression in salt-sensitive low-renin hypertension. Circulation 117, 1045–1054 (2008).

  39. 39.

    et al. Gene transfer of human guanosine 5′-triphosphate cyclohydrolase I restores vascular tetrahydrobiopterin level and endothelial function in low renin hypertension. Circulation 108, 1238–1245 (2003).

  40. 40.

    et al. Regulation of smooth muscle cell differentiation by AT-rich interaction domain transcription factors Mrf2alpha and Mrf2beta. Circ. Res. 91, 382–389 (2002).

  41. 41.

    et al. INTERSALT study findings. Public health and medical care implications. Hypertension 14, 570–577 (1989).

  42. 42.

    , & Urinary electrolyte excretion in 24 hours and blood pressure in the INTERSALT Study. I. Estimates of reliability. The INTERSALT Cooperative Research Group. Am. J. Epidemiol. 139, 927–939 (1994).

  43. 43.

    Hypertension Detection and Follow-up Program Cooperative Group. Variability of blood pressure and the results of screening in the hypertension detection and follow-up program. J. Chronic Dis. 31, 651–667 (1978).

  44. 44.

    et al. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat. Genet. 40, 768–775 (2008).

  45. 45.

    et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat. Genet. 41, 25–34 (2009).

  46. 46.

    et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat. Genet. 40, 189–197 (2008).

  47. 47.

    & Mach 1.0: rapid haplotype reconstruction and missing genotype inference. Am. J. Hum. Genet. S79, 2290 (2006).

  48. 48.

    , , , & A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).

  49. 49.

    , , , & A fine-scale map of recombination rates and hotspots across the human genome. Science 310, 321–324 (2005).

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Acknowledgements

The authors would like to thank the many colleagues who contributed to collection and phenotypic characterization of the clinical samples, as well as genotyping and analysis of the GWA data. They would also especially like to thank those who agreed to participate in the studies. Major funding for the work described in the paper comes from the following (alphabetically): Academy of Finland (124243, 129322, 129494, 118065), AGAUR (SGR 2005/00577), Albert Påhlsson Research Foundation, Alexander-von-Humboldt Foundation (V-Fokoop-1113183), American Diabetes Association, AstraZeneca AB, AVIS Torino blood donor organization, Barts and The London Charity, Biocenter of University of Oulu, Board of the UMC Utrecht, British Heart Foundation (PG02/128, FS/05/061/19501, SP/04/002), Burroughs Wellcome Fund, CamStrad, Cancer Research United Kingdom, CIBER Epidemiología y Salud Pública, Commissariat à l'Energie Atomique, Compagnia di San Paolo to the ISI Foundation (Torino, Italy), Conservatoire National des Arts et Métiers, Crafoord Foundation, Donovan Family Foundation, Doris Duke Charitable Foundation, Dutch Kidney Foundation (E033), Dutch College of Healthcare Insurance Companies, Dutch Ministry of Health, Dutch Organisation of Health Care Research, ENGAGE (HEALTH-F4-2007-201413), Ernhold Lundströms Research Foundation, Estonian Ministry of Education and Science (0182721s06), EURO-BLCS, European Commission (QLG1-CT-2000-01643, LSHM-CT-2007-037273), European Commission-Europe Against Cancer (AEP/90/05), European Union (FP-6 LSHM-CT-2003-503041, FP-6 LSHM CT 2006 037697), European Society for the Study of Diabetes, Faculty of Biology and Medicine of Lausanne, Switzerland, Fannie E. Rippel Foundation, Finnish Foundation for Cardiovascular Research, FIS (CP05/00290), Fundació Marató Tv3, German Federal Ministry of Education and Research (01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012, 01EZ0874), German National Genome Research Network, German Research Center for Environmental Health, (Neuherberg, Germany), Giorgi-Cavaglieri Foundation, GlaxoSmithKline, Guy's & St. Thomas' NHS Foundation Trust, Health Research and Development Council of the Netherlands (2100.0008, 2100.0042), Helmholtz Zentrum München, Hulda and Conrad Mossfelt Foundation, Institut National de la Recherche Agronomique, Institut National de la Santé et de la Recherche Médicale, Italian Association for Research on Cancer, Italian Ministry of Health (110.1RS97.71), Italian National Research Council, Juvenile Diabetes Research Fund, King Gustaf V and Queen Victoria Foundation, King's College London and King's College Hospital NHS Foundation Trust, Knut and Alice Wallenberg Foundation, Lennart Hanssons Memorial Fund, LK Research Funds, Massachusetts General Hospital Cardiovascular Research Center and Department of Medicine, Medical Faculty of Lund University and Malmö University Hospital, Medical Research Council of the UK (G0000934, G0501942, G9521010D), Medical Research Council-GlaxoSmithKline (85374), MedStar Research Institute, Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (RD06/0009, CP05/290, PI061254, CIBERESP), Ministry of Cultural Affairs and Social Ministry (Federal State of Mecklenburg-West Pomerania), National Institute for Health Research (NIHR), National Institute for Health Research Cambridge Biomedical Research Centre, Novartis Institute for Biomedical Research, NWO VENI (916.76.170), Province of Utrecht, Region Skane, Siemens Healthcare (Erlangen, Germany), Sigrid Juselius Foundation, Stockholm County Council (562183), Support for Science Funding programme, Swedish Heart and Lung Foundation, Swedish Medical Research Council, Swedish National Research Council, Swedish Research Council (8691), Swiss National Science Foundation (33CSO-122661, 310030-112552, 3100AO-116323/1, PROSPER 3200BO-111362/1, 3233BO-111361/1), UNIL, University of Utrecht, US National Institutes of Health (U01DK062418, K23HL80025, DK062370, DK072193, U54DA021519, 1Z01HG000024, N01AG-916413, N01AG-821336, 263MD916413, 263MD821336, Intramural NIA, R01HL087676, K23HL083102, U54RR020278, R01HL056931, P30ES007033, R01HL087679, RL1MH083268, 263-MA-410953, NO1-AG-1-2109, N01-HD-1-3107), WCRF (98A04, 2000/30), Wellcome Trust (068545/Z/02, 076113/B/04/Z, 079895, 070191/Z/03/Z, 077016/Z/05/Z, WT088885/Z/09/Z).

Author information

Author notes

    • Christopher Newton-Cheh
    • , Toby Johnson
    • , Vesela Gateva
    • , Martin D Tobin
    • , Paul Elliott
    • , Gonçalo R Abecasis
    • , Mark Caulfield
    •  & Patricia B Munroe

    These authors contributed equally to this work.

Affiliations

  1. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Christopher Newton-Cheh
    • , Benjamin F Voight
    • , Sekar Kathiresan
    •  & David Altshuler
  2. Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Christopher Newton-Cheh
    •  & Sekar Kathiresan
  3. Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Christopher Newton-Cheh
    • , Benjamin F Voight
    • , Gabriel J Crawford
    • , Sekar Kathiresan
    •  & David Altshuler
  4. Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.

    • Toby Johnson
    • , Jacques S Beckmann
    •  & Sven Bergmann
  5. University Institute for Social and Preventative Medicine, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne, Switzerland.

    • Toby Johnson
    •  & Murielle Bochud
  6. Swiss Institute of Bioinformatics, Lausanne, Switzerland.

    • Toby Johnson
    •  & Sven Bergmann
  7. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.

    • Vesela Gateva
    • , Laura J Scott
    • , Michael Boehnke
    • , Anne U Jackson
    • , Heather M Stringham
    •  & Cristen J Willer
  8. Departments of Health Sciences and Genetics, Adrian Building, University of Leicester, University Road, Leicester, UK.

    • Martin D Tobin
    • , Louise V Wain
    •  & Paul R Burton
  9. Department of Epidemiology and Public Health, Imperial College London, St. Mary's Campus, Norfolk Place, London, UK.

    • Lachlan Coin
    • , John C Chambers
    • , Paolo Vineis
    • , Paul F O'Reilly
    • , Marjo-Riitta Jarvelin
    •  & Paul Elliott
  10. Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.

    • Samer S Najjar
    •  & Edward G Lakatta
  11. MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

    • Jing Hua Zhao
    • , Jian'an Luan
    • , Manjinder S Sandhu
    • , Nita G Forouhi
    • , Nicholas J Wareham
    •  & Ruth JF Loos
  12. Cambridge-Genetics of Energy Metabolism (GEM) Consortium, Cambridge, UK.

    • Jing Hua Zhao
    • , Kay-Tee Khaw
    • , Inês Barroso
    • , Manjinder S Sandhu
    • , Robert N Luben
    • , Panos Deloukas
    • , Sheila A Bingham
    • , Nicholas J Wareham
    •  & Ruth JF Loos
  13. Centre National de Génotypage, Evry Cedex, France.

    • Simon C Heath
    • , Ivo G Gut
    • , G Mark Lathrop
    •  & Diana Zelenika
  14. Pontificia Universidad Católica de Chile, Facultad de Matemáticas, Santiago, Chile.

    • Susana Eyheramendy
  15. Institute of Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.

    • Susana Eyheramendy
    • , Angela Döring
    • , Christian Gieger
    • , Thomas Illig
    •  & H Erich Wichmann
  16. Division of Community Health Sciences, St. George's, University of London, London, UK.

    • Konstantinos Papadakis
    • , David Hadley
    •  & David P Strachan
  17. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • Feng Zhang
    • , Nicole Soranzo
    • , Frances M Williams
    • , Guangju Zhai
    •  & Tim D Spector
  18. Department of Cardiovascular Medicine, University of Oxford, Oxford, UK.

    • Martin Farrall
    • , Anuj Goel
    • , John F Peden
    •  & Hugh Watkins
  19. The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, UK.

    • Martin Farrall
    • , Katherine S Elliott
    • , Eleftheria Zeggini
    • , Mark I McCarthy
    • , Anuj Goel
    • , John F Peden
    •  & Hugh Watkins
  20. Medstar Research Institute, Baltimore, Maryland, USA.

    • Toshiko Tanaka
  21. Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, USA.

    • Toshiko Tanaka
    •  & Luigi Ferrucci
  22. Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    • Chris Wallace
    • , Stephen J Newhouse
    • , Mark Caulfield
    •  & Patricia B Munroe
  23. The Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    • Chris Wallace
    • , Stephen J Newhouse
    • , Mark Caulfield
    •  & Patricia B Munroe
  24. Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge, UK.

    • Chris Wallace
  25. Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK.

    • Kay-Tee Khaw
    • , Manjinder S Sandhu
    •  & Robert N Luben
  26. Department of Clinical Sciences, Lund University, Malmö University Hospital, Malmö, Sweden.

    • Peter Nilsson
    • , Marju Orho-Melander
    • , Göran Berglund
    •  & Olle Melander
  27. Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

    • Pim van der Harst
    •  & Wiek H van Gilst
  28. ISI Foundation (Institute for Scientific Interchange), Villa Gualino, Torino, Italy.

    • Silvia Polidoro
    • , Alessandra Allione
    • , Alessandra Di Gregorio
    • , Simonetta Guarrera
    • , Fulvio Ricceri
    • , Valeria Romanazzi
    • , Paolo Vineis
    •  & Giuseppe Matullo
  29. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.

    • Diederick E Grobbee
    • , N Charlotte Onland-Moret
    • , Michiel L Bots
    • , Cuno S Uiterwaal
    • , Yvonne T van der Schouw
    •  & Mattijs E Numans
  30. Complex Genetics Section, Department of Medical Genetics-DBG, University Medical Center Utrecht, Utrecht, The Netherlands.

    • N Charlotte Onland-Moret
  31. Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.

    • Alexander Teumer
    • , Florian Ernst
    • , Georg Homuth
    •  & Uwe Völker
  32. Cardiovascular Epidemiology and Genetics, Institut Municipal d'Investigació Mèdica, Barcelona, Spain.

    • Gavin Lucas
    • , Jaume Marrugat
    • , Isaac Subirana
    •  & Roberto Elosua
  33. Department of Medicine, University of Kuopio, Kuopio, Finland.

    • Johanna Kuusisto
    •  & Markku Laakso
  34. ALSPAC Laboratory, Department of Social Medicine, University of Bristol, Bristol, UK.

    • Wendy L McArdle
  35. Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

    • Morris Brown
  36. BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.

    • Anna Dominiczak
    •  & John M Connell
  37. Department of Cardiovascular Science, University of Leicester, Glenfield Hospital, Leicester, UK.

    • Nilesh J Samani
  38. Aberdeen Royal Infirmary, Aberdeen, UK.

    • John Webster
  39. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Eleftheria Zeggini
    • , Inês Barroso
    • , Leena Peltonen
    • , Panos Deloukas
    •  & Nicole Soranzo
  40. Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.

    • Jacques S Beckmann
  41. Genetics Division, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.

    • Noha Lim
    • , Kijoung Song
    • , Dawn M Waterworth
    • , Xin Yuan
    •  & Vincent Mooser
  42. Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.

    • Peter Vollenweider
    •  & Gerard Waeber
  43. Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, University Hospital, Malmö, Sweden.

    • Leif Groop
  44. Lund University, Malmö, Sweden.

    • Leif Groop
  45. Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy.

    • Alessandra Di Gregorio
    • , Valeria Romanazzi
    •  & Giuseppe Matullo
  46. Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy.

    • Salvatore Panico
  47. Unit of Cancer Epidemiology, University of Turin and Centre for Cancer Epidemiology and Prevention (CPO Piemonte), Turin, Italy.

    • Carlotta Sacerdote
  48. National Institute for Welfare and Health, Helsinki, Finland.

    • Pekka Jousilahti
    • , Markus Perola
    •  & Veikko Salomaa
  49. Institute for Molecular Medicine Finland FIMM, University of Helsinki and National Public Health Institute, Finland.

    • Markus Perola
    •  & Leena Peltonen
  50. Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland, USA.

    • Lori L Bonnycastle
    • , Francis S Collins
    •  & Mario A Morken
  51. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Karen L Mohlke
  52. Diabetes Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland.

    • Timo T Valle
    •  & Jaakko Tuomilehto
  53. Physiology and Biophysics, University of Southern California School of Medicine, Los Angeles, California, USA.

    • Richard N Bergman
  54. Institute of Human Genetics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.

    • Thomas Meitinger
    •  & Arne Pfeufer
  55. Institute of Human Genetics, Technische Universität München, Munich, Germany.

    • Thomas Meitinger
    •  & Arne Pfeufer
  56. Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.

    • Elin Org
    •  & Maris Laan
  57. Ludwig Maximilians University, IBE, Chair of Epidemiology, Munich, Germany.

    • H Erich Wichmann
  58. Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Christopher J O'Donnell
  59. Framingham Heart Study and National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA.

    • Christopher J O'Donnell
  60. Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington, USA.

    • Stephen M Schwartz
    •  & David S Siscovick
  61. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Stephen M Schwartz
    •  & David S Siscovick
  62. CIBER Epidemiología y Salud Pública, Barcelona, Spain.

    • Isaac Subirana
    •  & Roberto Elosua
  63. Center for Neurobehavioral Genetics, Gonda Center, University of California Los Angeles, Los Angeles, California, USA.

    • Nelson B Freimer
  64. Department of Clinical Sciences/Obstetrics and Gynecology, University of Oulu, Oulu, Finland.

    • Anna-Liisa Hartikainen
    •  & Anneli Pouta
  65. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.

    • Mark I McCarthy
  66. Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK.

    • Mark I McCarthy
  67. Department of Child and Adolescent Health, National Public Health Institute (KTL), Oulu, Finland.

    • Anneli Pouta
    •  & Marjo-Riitta Jarvelin
  68. Division of Nephrology, Department of Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

    • Paul E de Jong
    •  & Gerjan Navis
  69. Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

    • Harold Snieder
  70. Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK.

    • Robert Clarke
  71. Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.

    • Anders Hamsten
  72. Leibniz-Institut für Arterioskleroseforschung an der Universität Münster, Münster, Germany.

    • Udo Seedorf
  73. Molecular Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

    • Ann-Christine Syvänen
  74. Consorzio Mario Negri Sud, Via Nazionale, Santa Maria Imbaro (Chieti), Italy.

    • Giovanni Tognoni
  75. Istituto di Neurogenetica e Neurofarmacologia, CNR, Monserrato, Cagliari, Italy.

    • Serena Sanna
    •  & Manuela Uda
  76. Department of Epidemiology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.

    • Paul Scheet
  77. Laboratory of Genetics, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.

    • David Schlessinger
  78. Unitá Operativa Geriatria, Istituto Nazionale Ricovero e Cura per Anziani (INRCA) IRCCS, Rome, Italy.

    • Angelo Scuteri
  79. Department of Internal Medicine B, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.

    • Marcus Dörr
    • , Stephan B Felix
    •  & Thorsten Reffelmann
  80. Institute for Community Medicine, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.

    • Roberto Lorbeer
    •  & Henry Völzke
  81. Institute of Physiology, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.

    • Rainer Rettig
  82. U557 Institut National de la Santé et de la Recherche Médicale, U1125 Institut National de la Recherche Agronomique, Université Paris 13, Bobigny Cedex, France.

    • Pilar Galan
    •  & Serge Hercberg
  83. MRC Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Cambridge, UK.

    • Sheila A Bingham
  84. National Heart and Lung Institute, Imperial College London, London, UK.

    • Jaspal S Kooner
  85. Geriatric Rehabilitation Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy.

    • Stefania Bandinelli
  86. Department of Public Health, University of Helsinki, Helsinki, Finland.

    • Jaakko Tuomilehto
  87. South Ostrobothnia Central Hospital, Seinäjoki, Finland.

    • Jaakko Tuomilehto
  88. Department of Medicine and Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • David Altshuler
  89. Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • David Altshuler
  90. U872 Institut National de la Santé et de la Recherche Médicale, Faculté de Médecine Paris Descartes, Paris Cedex, France.

    • Pierre Meneton
  91. Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Jarvelin
  92. Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.

    • Gonçalo R Abecasis

Consortia

  1. Wellcome Trust Case Control Consortium

    A full list of authors is provided in the Supplementary Note.

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Contributions

Author contributions are listed in alphabetical order.

Project conception, design, management: ARYA: M.L.B., C.S.U.; BLSA: L.F.; B58C-T1DGC: D.P.S.; B58C-WTCCC: D.P.S.; BRIGHT: M. Brown, M.C., J.M.C., A. Dominiczak, M.F., P.B.M., N.J.S., J.W.; CoLaus: J.S.B., S. Bergmann, M. Bochud, V.M. (PI), P. Vollenweider (PI), G.W., D.M.W.; DGI: D.A., C.N.-C., L.G.; EPIC-Norfolk-GWAS: I.B., P.D., R.J.F.L., M.S.S., N.J.W., J.H.Z. EPIC-Italy: S. Polidoro, P. Vineis. Fenland Study: R.J.F.L., N.G.F., N.J.W.; Finrisk97: L.P., V.S.; FUSION: R.N.B., M. Boehnke, F.S.C., K.L.M., L.J.S., T.T.V., J.T.; InCHIANTI: S. Bandinelli., L.F.; KORA: A. Döring, C.G., T.I., M. Laan, T.M., E.O., A. Pfeufer, H.E.W. (PI); LOLIPOP: J.C.C., P.E., J.S.K. (PI); MDC-CC: G.B., O.M.; MPP: G.B., O.M.; MIGen: D.A., R.E., S.K., J.M., O.M., C.J.O., V.S., S.M.S., D.S.S.; METSIM: J.K., M. Laakso; NFBC1966: P.E., M.-R.J.; PREVEND: P.E.d.J. (PI), G.N., W.H.v.G.; PROCARDIS: R.C., M.F., A.H., J.F.P., U.S., G.T., H.W. (PI); PROSPECT-EPIC. N.C.O.-M., Y.T.v.d.S.; SardiNIA: E.G.L., D.S.; SHIP: M.D., S.B.F., G.H., R.L., T.R., R.R., U.V., H.V.; SUVIMAX: P.M.; TwinsUK: P.D., T.D.S. (PI); UHP: D.E.G., M.E.N.

Phenotype collection, data management: ARYA: M.L.B., C.S.U.; B58C-T1DGC: D.H., W.L.M., D.P.S.; B58C-WTCCC: D.H., K.P., D.P.S.; BRIGHT: M. Brown, M.C., J.M.C., A. Dominiczak, M.F., P.B.M., N.J.S., J.W.; CoLaus: G.W.; DGI: L.G., O.M.; EPIC-Italy: P. Vineis (PI); Finrisk97: P.J., M.P., V.S.; FUSION: J.T., T.T.V.; KORA: A. Döring, C.G., T.I.; MDC-CC: O.M.; MPP: O.M., P.N.; MIGen: D.A., R.E., S.K., J.M., O.M., C.J.O., S.M.S., D.S.S., V.S.; NFBC1966: A.-L.H., M.-R.J., A. Pouta; PREVEND: P.E.d.J., G.N., P.v.d.H., W.H.v.G.; PROCARDIS: R.C., A.H., U.S., G.T.; PROSPECT-EPIC: N.C.O.-M., Y.T.v.d.S.; SardiNIA: S.S.N., A.S.; SHIP: M.D., R.L., R.R., H.V.; SUVIMAX: P.G., S.H.; TwinsUK: F.M.W.; UHP: D.E.G., M.E.N.

Genome-wide, validation genotyping: B58C-T1DGC: W.L.M.; B58C-WTCCC: W.L.M.; DGI: D.A., O.M., M.O.-M.; EPIC-Norfolk-GWAS: I.B., P.D., N.J.W., J.H.Z.; EPIC-Norfolk-replication: S.A.B., K.-T.K., R.J.F.L., R.N.L., N.J.W.; EPIC-Italy: A.A., A.D.G., S.G., G.M., V.R.; Finrisk97: G.J.C., C.N.-C.; FUSION: L.L.B., M.A.M.; KORA: T.I., T.M., E.O., A. Pfeufer; MDC-CC: O.M., M.O.-M.; MPP: O.M., M.O.-M.; NFBC1966: P.E., N.B.F., M.-R.J., M.I.M., L.P. ; PREVEND: G.N., P.v.d.H.; W.H.v.G.; PROCARDIS: S.C.H., G.M.L., A.-C.S.; SardiNIA: M.U.; SHIP: F.E., G.H., A.T., U.V.; SUVIMAX: I.G.G., S.C.H., G.M.L., D.Z.; TwinsUK: P.D., N.S.

Data analysis: BLSA: T.T.; B58C-T1DGC: D.H., S.H., D.P.S.; B58C-WTCCC: P.R.B., D.H., K.P., D.P.S, M.D.T.; BRIGHT: S.J.N., C.W., E.Z.; CoLaus: S. Bergmann, M. Bochud, T.J., N.L., K.S., X.Y., DGI: O.M., C.N.-C., M.O.-M., B.F.V.; EPIC-Norfolk-GWAS: R.J.F.L., J.H.Z.; EPIC-Norfolk-replication: S.A.B., K.-T.K., R.J.F.L., R.N.L., N.J.W.; EPIC-Italy: S.G., G.M., S. Panico, S. Polidoro, F.R., C.S., P. Vineis; Fenland Study: J.L.; Finrisk97: C.N.-C.; FUSION: A.U.J., L.J.S., H.M.S., C.J.W.; InCHIANTI: T.T.; KORA: S.E., C.G., M. Laan, E.O.; LOLIPOP: J.C.C.; MDC-CC: O.M., M.O.-M.; MPP: O.M., M.O.-M.; MIGen: R.E., G.L., I.S., B.F.V.; NFBC1966: L.C., P.F.O.; PREVEND: H.S., P.v.d.H.; PROCARDIS: M.F., A.G., J.F.P.; SardiNIA: V.G., S.S., P.S.; SHIP: F.E., G.H., A.T., U.V.; SUVIMAX: S.C.H., T.J., P.M.; TwinsUK: N.S., F.Z., G.Z.

Analysis group: G.R.A., M.C., V.G., T.J., P.B.M., C.N.-C., M.D.T., L.V.W.

Writing group: G.R.A., M.C., P.E., V.G., T.J., P.B.M., C.N.-C., M.D.T.

Competing interests

The following authors declare the following potential conflicts of interest: N.L., V.M., K.S., D.M.W. and X.Y. are all full-time employees at GlaxoSmithKline. P.Vollenweider and G.W received financial support from GlaxoSmithKline to assemble the CoLaus study. No other authors reported conflicts of interest.

Corresponding authors

Correspondence to Christopher Newton-Cheh or Gonçalo R Abecasis or Mark Caulfield or Patricia B Munroe.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1 and 2, Supplementary Tables 1–4, Supplementary Methods and Supplementary Note

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DOI

https://doi.org/10.1038/ng.361

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