Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease

Journal name:
Nature Genetics
Volume:
43,
Pages:
333–338
Year published:
DOI:
doi:10.1038/ng.784
Received
Accepted
Published online

We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 × 10−8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.

At a glance

Figures

  1. Graphical summary (Manhattan plot) of genome-wide association results.
    Figure 1: Graphical summary (Manhattan plot) of genome-wide association results.

    The x axis represents the genome in physical order; the y axis shows −log10 P for all SNPs. Data from the discovery phase are shown in circles, and data from the combined discovery and replication phases are shown in stars. Genes at the significant loci are listed above the signals. Known loci are shown in red and newly discovered loci are shown in blue.

  2. Example of overlapping association signals for multiple traits at the ABO gene region on chromosome 9q34.
    Figure 2: Example of overlapping association signals for multiple traits at the ABO gene region on chromosome 9q34.

    In the upper panel, the association signal for coronary disease at the ABO gene region in CARDIoGRAM and the positions and rs numbers of SNPs in this region are shown. The size of the boxes illustrates the number of individuals available for this respective SNP. In the lower panel, all SNPs with P values at the genome-wide significance level of P < 5 × 10−8 based on the National Human Genome Research Institute GWAS catalog (accessed on 28 June 2010) for all diseases and traits are shown. The degree of linkage disequilibrium (r2) between the lead SNPs for coronary disease and the other traits is reflected by the color of the squares (upper panel) and the small bars (lower panel), from dark red (high LD) to faint red (low LD). SI/CH, sitosterol normalized to cholesterol; CA/CH, campesterol normalized to cholesterol; ALP, alkaline phosphatase; ACE, angiotensin converting enzyme; FVIII, coagulation factor VIII; vWF, von Willebrand factor.

References

  1. Marenberg, M.E., Risch, N., Berkman, L.F., Floderus, B. & de Faire, U. Genetic susceptibility to death from coronary heart disease in a study of twins. N. Engl. J. Med. 330, 10411046 (1994).
  2. Schunkert, H., Erdmann, J. & Samani, N.J. Genetics of myocardial infarction: a progress report. Eur. Heart J. 31, 918925 (2010).
  3. Preuss, M. et al. Design of the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) study: a genome-wide association meta-analysis involving more than 22,000 cases and 60,000 controls. Circ. Cardiovasc. Genet. 3, 475483 (2010).
  4. Clarke, R. et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N. Engl. J. Med. 361, 25182528 (2009).
  5. Trégouët, D.A. et al. Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease. Nat. Genet. 41, 283285 (2009).
  6. Psaty, B.M. et al. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium: design of prospective meta-analyses of genome-wide association studies from 5 cohorts. Circ. Cardiovasc. Genet. 2, 7380 (2009).
  7. Nitz, I. et al. Association analyses of GIP and GIPR polymorphisms with traits of the metabolic syndrome. Mol. Nutr. Food Res. 51, 10461052 (2007).
  8. Emilsson, V. et al. Genetics of gene expression and its effect on disease. Nature 452, 423428 (2008).
  9. Zhong, H. et al. Liver and adipose expression associated SNPs are enriched for association to type 2 diabetes. PLoS Genet. 6, e1000932 (2010).
  10. Ge, B. et al. Global patterns of cis variation in human cells revealed by high-density allelic expression analysis. Nat. Genet. 41, 12161222 (2009).
  11. Hindorff, L.A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl. Acad. Sci. USA 106, 93629367 (2009).
  12. Brown, M.S. & Goldstein, J.L. Expression of the familial hypercholesterolemia gene in heterozygotes: mechanism for a dominant disorder in man. Science 185, 6163 (1974).
  13. Linsel-Nitschke, P. et al. Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease—a Mendelian Randomisation study. PLoS ONE 3, e2986 (2008).
  14. Musunuru, K. et al. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature 466, 714719 (2010).
  15. Linsel-Nitschke, P., Samani, N.J. & Schunkert, H. Sorting out cholesterol and coronary artery disease. N. Engl. J. Med. 363, 24622463 (2010).
  16. Manolio, T.A. et al. Finding the missing heritability of complex diseases. Nature 461, 747753 (2009).
  17. Wilson, P.W. et al. Prediction of coronary heart disease using risk factor categories. Circulation 97, 18371847 (1998).
  18. Ripatti, S. et al. A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses. Lancet 376, 13931400 (2010).
  19. Assimes, T.L. et al. Susceptibility locus for clinical and subclinical coronary artery disease at chromosome 9p21 in the multi-ethnic ADVANCE study. Hum. Mol. Genet. 17, 23202328 (2008).
  20. Helgadottir, A. et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316, 14911493 (2007).
  21. Samani, N.J. et al. Genomewide association analysis of coronary artery disease. N. Engl. J. Med. 357, 443453 (2007).
  22. Erdmann, J. et al. Genome-wide association study identifies a new locus for coronary artery disease on chromosome 10p11.23. Eur. Heart J. 32, 158168 (2011).
  23. Erdmann, J. et al. New susceptibility locus for coronary artery disease on chromosome 3q22.3. Nat. Genet. 41, 280282 (2009).
  24. Winkelmann, B.R. et al. Rationale and design of the LURIC study—a resource for functional genomics, pharmacogenomics and long-term prognosis of cardiovascular disease. Pharmacogenomics 2, S1S73 (2001).
  25. Lehrke, M. et al. CXCL16 is a marker of inflammation, atherosclerosis and acute coronary syndromes in humans. J. Am. Coll. Cardiol. 49, 442449 (2007).
  26. Kathiresan, S. et al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat. Genet. 41, 334341 (2009).
  27. McPherson, R. et al. A common allele on chromosome 9 associated with coronary heart disease. Science 316, 14881491 (2007).
  28. WTCCC. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661678 (2007).
  29. Anonymous. The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. The ARIC investigators. Am. J. Epidemiol. 129, 687702 (1989).
  30. Wichmann, H.E., Gieger, C. & Illig, T. KORA-gen–resource for population genetics, controls and a broad spectrum of disease phenotypes. Gesundheitswesen 67 Suppl 1, S26S30 (2005).
  31. Pastinen, T. & Hudson, T.J. Cis-acting regulatory variation in the human genome. Science 306, 647650 (2004).
  32. Li, Y., Willer, C.J., Ding, J., Scheet, P. & Abecasis, G.R. MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet. Epidemiol. 34, 816834 (2010).
  33. Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906913 (2007).
  34. Servin, B. & Stephens, M. Imputation-based analysis of association studies: candidate regions and quantitative traits. PLoS Genet. 3, e114 (2007).
  35. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 9971004 (1999).
  36. Bagos, P.G. A unification of multivariate methods for meta-analysis of genetic association studies. Stat. Appl. Genet. Mol. Biol. 7, Article31 (2008).
  37. Bagos, P.G. & Nikolopoulos, G.K. A method for meta-analysis of case-control genetic association studies using logistic regression. Stat. Appl. Genet. Mol. Biol. 6, Article17 (2007).
  38. Gudbjartsson, D.F. et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat. Genet. 41, 342347 (2009).
  39. Kathiresan, S. et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat. Genet. 41, 5665 (2009).

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Author information

  1. These authors contributed equally to this work.

    • Heribert Schunkert,
    • Inke R König,
    • Sekar Kathiresan,
    • Muredach P Reilly,
    • Themistocles L Assimes,
    • Hilma Holm,
    • Christopher J O'Donnell,
    • Ruth McPherson,
    • Jeanette Erdmann &
    • Nilesh J Samani

Affiliations

  1. Universität zu Lübeck, Medizinische Klinik II, Lübeck, Germany.

    • Heribert Schunkert,
    • Michael Preuss,
    • Zouhair Aherrahrou,
    • Patrick Diemert,
    • Jennifer Freyer,
    • Wolfgang Lieb,
    • Christina Loley,
    • Seraya Maouche,
    • Janja Nahrstaedt,
    • Stephanie Tennstedt,
    • Christina Willenborg &
    • Jeanette Erdmann
  2. Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany.

    • Inke R König,
    • Michael Preuss,
    • Christina Loley,
    • Janja Nahrstaedt,
    • Arne Schillert,
    • Christina Willenborg &
    • Andreas Ziegler
  3. Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Sekar Kathiresan &
    • Kiran Musunuru
  4. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Sekar Kathiresan,
    • Kiran Musunuru &
    • Benjamin F Voight
  5. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Sekar Kathiresan,
    • David Altshuler,
    • Kiran Musunuru &
    • Benjamin F Voight
  6. The Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Muredach P Reilly &
    • Daniel J Rader
  7. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.

    • Themistocles L Assimes,
    • Joshua W Knowles &
    • Thomas Quertermous
  8. deCODE genetics, Reykjavik, Iceland.

    • Hilma Holm,
    • Solveig Gretarsdottir,
    • Jeffrey R Gulcher,
    • Augustine Kong,
    • Gudmar Thorleifsson,
    • Kari Stefansson &
    • Unnur Thorsteinsdottir
  9. The John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

    • Alexandre F R Stewart,
    • Robert Roberts &
    • Ruth McPherson
  10. University of Texas Health Science Center, Human Genetics Center, Houston, Texas, USA.

    • Maja Barbalic &
    • Eric Boerwinkle
  11. Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Christian Gieger,
    • Angela Doering,
    • Thomas Illig,
    • Christa Meisinger,
    • Annette Peters &
    • H-Erich Wichmann
  12. Hudson Alpha Institute, Huntsville, Alabama, USA.

    • Devin Absher
  13. Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA.

    • Hooman Allayee
  14. Department of Molecular Biology and Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • David Altshuler
  15. Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada.

    • Sonia S Anand
  16. Department of Medicine, Landspitali University Hospital, Reykjavik, Iceland.

    • Karl Andersen &
    • Gudmundur Thorgeirsson
  17. University of Iceland, Faculty of Medicine, Reykjavik, Iceland.

    • Karl Andersen,
    • Vilmundur Gudnason,
    • Albert Smith,
    • Gudmundur Thorgeirsson,
    • Kari Stefansson &
    • Unnur Thorsteinsdottir
  18. Cardiovascular Department, Intermountain Medical Center, Cardiology Division, University of Utah, Salt Lake City, Utah, USA.

    • Jeffrey L Anderson,
    • John F Carlquist,
    • Benjamin D Horne &
    • Joseph B Muhlestein
  19. Division of Cardiology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.

    • Diego Ardissino
  20. LIGHT Research Institute, Faculty of Medicine and Health, University of Leeds, Leeds, UK.

    • Stephen G Ball
  21. Division of Cardiovascular and Neuronal Remodelling, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK.

    • Stephen G Ball &
    • Alistair S Hall
  22. Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK.

    • Anthony J Balmforth &
    • Christopher P Nelson
  23. Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester, UK.

    • Timothy A Barnes,
    • Peter S Braund,
    • Veryan Codd,
    • Michael A Kaiser,
    • Maciej Tomaszewski,
    • Alison H Goodall &
    • Nilesh J Samani
  24. The Johns Hopkins University School of Medicine, Division of General Internal Medicine, Baltimore, Maryland, USA.

    • Diane M Becker &
    • Lewis C Becker
  25. Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.

    • Klaus Berger
  26. Cardiovascular Health Resarch Unit and Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Joshua C Bis,
    • Stephen M Schwartz &
    • David S Siscovick
  27. Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.

    • S Matthijs Boekholdt &
    • Suthesh Sivapalaratnam
  28. Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands.

    • S Matthijs Boekholdt
  29. Clinical Pharmacology Unit, University of Cambridge, Cambridge, UK.

    • Morris J Brown
  30. Cardiovascular Research Institute, Medstar Health Research Institute, Washington Hospital Center, Washington, DC, USA.

    • Mary Susan Burnett,
    • Joseph M Devaney &
    • Stephen E Epstein
  31. Department of Cardiology, University Hospital Gasthuisberg, Leuven, Belgium.

    • Ian Buysschaert
  32. Vesalius Research Center, VIB-K.U.Leuven, Leuven, Belgium.

    • Ian Buysschaert &
    • Diether Lambrechts
  33. Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

    • Li Chen
  34. Institute of Human Genetics, University of Bonn, Bonn, Germany.

    • Sven Cichon,
    • Thomas W Mühleisen &
    • Markus M Nöthen
  35. Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.

    • Sven Cichon,
    • Thomas W Mühleisen &
    • Markus M Nöthen
  36. Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany.

    • Sven Cichon
  37. The Cardiovascular Research Methods, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

    • Robert W Davies &
    • George A Wells
  38. Department of Dietetics-Nutrition, Harokopio University, Athens, Greece.

    • George Dedoussis
  39. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Abbas Dehghan,
    • Albert Hofman,
    • Andre G Uitterlinden &
    • Jaqueline C M Witteman
  40. Member of Netherlands Consortium for Healthy Aging (NCHA) sponsored by Netherlands Genomics Initiative (NGI), Leiden, The Netherlands.

    • Abbas Dehghan,
    • Andre G Uitterlinden &
    • Jaqueline C M Witteman
  41. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Serkalem Demissie &
    • L Adrienne Cupples
  42. National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Serkalem Demissie,
    • L Adrienne Cupples &
    • Christopher J O'Donnell
  43. Department of Human Genetics, McGill University, Montreal, Quebec, Canada.

    • Ron Do &
    • James C Engert
  44. Klinikum Grosshadern, Munich, Germany.

    • Sandra Eifert &
    • H-Erich Wichmann
  45. Klinik für Innere Medizin, Kreiskrankenhaus Rendsburg, Rendsburg, Germany.

    • Nour Eddine El Mokhtari
  46. Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.

    • Stephen G Ellis &
    • W H Wilson Tang
  47. Cardiovascular Epidemiology and Genetics Group, Institut Municipal d'Investigació Mèdica, Ciber Epidemiología y Salud Pública (CIBERSP), Barcelona, Spain.

    • Roberto Elosua
  48. Department of Medicine, McGill University, Montreal, Canada.

    • James C Engert
  49. Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

    • Ulf de Faire,
    • Bruna Gigante &
    • Karin Leander
  50. Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.

    • Ulf de Faire &
    • Bruna Gigante
  51. Klinik und Poliklinik für Innere Medizin II, Regensburg, Germany.

    • Marcus Fischer,
    • Klaus Stark &
    • Christian Hengstenberg
  52. University of Minnesota School of Public Health, Division of Epidemiology and Community Health, School of Public Health (A.R.F.), Minneapolis, Minnesota, USA.

    • Aaron R Folsom
  53. Department of Medicine, University of Verona, Verona, Italy.

    • Domenico Girelli,
    • Nicola Martinelli &
    • Oliviero Olivieri
  54. Icelandic Heart Association, Kopavogur, Iceland.

    • Vilmundur Gudnason &
    • Albert Smith
  55. The Blavatnik School of Computer Science, Tel-Aviv University, Tel-Aviv, Israel.

    • Eran Halperin
  56. Department of Molecular Microbiology and Biotechnology, Tel-Aviv University, Tel-Aviv, Israel.

    • Eran Halperin
  57. International Computer Science Institute, Berkeley, California, USA.

    • Eran Halperin
  58. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Naomi Hammond,
    • Catherine Rice,
    • Nicole Soranzo,
    • Kathy Stirrups,
    • Willem H Ouwehand &
    • Panos Deloukas
  59. Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

    • Stanley L Hazen
  60. Division of Research, Kaiser Permanente of Northern California, Oakland, California, USA.

    • Carlos Iribarren
  61. Surgery Department, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.

    • Gregory T Jones &
    • Andre M van Rij
  62. Department of Cardiology C5-P, Leiden University Medical Center, Leiden, The Netherlands.

    • J Wouter Jukema
  63. Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands.

    • J Wouter Jukema
  64. Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Lee M Kaplan
  65. Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

    • John J P Kastelein
  66. Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK.

    • Kay-Tee Khaw
  67. 1st Cardiology Department, Onassis Cardiac Surgery Center, Athens, Greece.

    • Genovefa Kolovou
  68. Science Center, Tampere University Hospital, Tampere, Finland.

    • Reijo Laaksonen
  69. Montreal Heart Institute, Montréal, Québec, Canada.

    • Guillaume Lettre
  70. Département de Médecine, Université de Montréal, succursale Centre-ville, Montréal, Québec, Canada.

    • Guillaume Lettre
  71. Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Mingyao Li &
    • Liming Qu
  72. Clinical Neurosciences Division, School of Medicine, University of Southampton, Southampton, UK.

    • Andrew J Lotery
  73. Southampton Eye Unit, Southampton General Hospital, Southampton, UK.

    • Andrew J Lotery
  74. Scientific Direction, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Cà Granda, Ospedale Maggiore Policlinico, Milano, Italy.

    • Pier M Mannucci
  75. Centre for Public Health, Queen's University Belfast, Institute of Clinical Science, Belfast, Ireland, UK.

    • Pascal P McKeown &
    • Chris C Patterson
  76. Institute of Human Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Umwelt und Gesundheit, Neuherberg, Germany.

    • Thomas Meitinger
  77. Institute of Human Genetics, Technische Universität München, Klinikum rechts der Isar, Munich, Germany.

    • Thomas Meitinger
  78. Department of Clinical Sciences, Hypertension and Cardiovascular Diseases, Scania University Hospital, Lund University, Malmö, Sweden.

    • Olle Melander
  79. Division of Cardiology, Azienda Ospedaliera Niguarda Ca'Granda, Milan, Italy.

    • Pier Angelica Merlini
  80. Genetics Division and Drug Discovery, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.

    • Vincent Mooser
  81. Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Thomas Morgan
  82. Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz, Johannes-Gutenberg Universität Mainz, Germany.

    • Thomas Münzel,
    • Philipp S Wild,
    • Tanja Zeller &
    • Stefan Blankenberg
  83. Emory University School of Medicine, Atlanta, Georgia, USA.

    • Riyaz S Patel &
    • Arshed A Quyyumi
  84. Cardiff University, Cardiff, Wales, UK.

    • Riyaz S Patel
  85. A. Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Medicine and Medical Specialties, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano and Luigi Villa Foundation, Milan, Italy.

    • Flora Peyvandi
  86. The Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Daniel J Rader
  87. Second Department of Cardiology, Attikon Hospital, School of Medicine, University of Athens, Athens, Greece.

    • Loukianos S Rallidis
  88. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.

    • Frits R Rosendaal &
    • Jaapjan D Snoep
  89. Department of Thrombosis and Haemostasis, Leiden University Medical Center, Leiden, The Netherlands.

    • Frits R Rosendaal
  90. Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.

    • Frits R Rosendaal
  91. Medizinische Klinik I, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany.

    • Diana Rubin
  92. Chronic Disease Epidemiology and Prevention Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.

    • Veikko Salomaa
  93. Department of Human Genetics and Cardiology, Leiden University Medical Center, Leiden, The Netherlands.

    • M Lourdes Sampietro
  94. Manjinder S. Sandhu, Genetic Epidemiology Group, Wellcome Trust Sanger Institute, Cambridge, UK.

    • Manj S Sandhu
  95. Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK.

    • Manj S Sandhu
  96. Pacific Biosciences, Menlo Park, California, USA.

    • Eric Schadt
  97. Sage Bionetworks, Palo Alto, California, USA.

    • Eric Schadt
  98. Institut für Klinische Molekularbiologie, Christian-Albrechts Universität, Kiel, Germany.

    • Arne Schäfer &
    • Stefan Schreiber
  99. Institute of Physiology and Biochemistry of Nutrition, Max Rubner-Institute, Kiel, Germany.

    • Jürgen Schrezenmeir
  100. Clinical Research Center Kiel, Kiel Innovation and Technology Center, Kiel, Germany.

    • Jürgen Schrezenmeir
  101. Cardiology Division, Leeds Teaching Hospitals National Health Service Trust, Leeds, UK.

    • Mohan Sivananthan
  102. Laboratory of Epidemiology, Demography and Biometry, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.

    • Tamara B Smith
  103. Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, Missouri, USA.

    • John A Spertus
  104. Leibniz-Institute for Arteriosclerosis Research, University of Münster, Münster, Germany.

    • Monika Stoll
  105. Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, UK.

    • Maciej Tomaszewski,
    • Alison H Goodall &
    • Nilesh J Samani
  106. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Andre G Uitterlinden
  107. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Benjamin F Voight
  108. Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

    • Nick J Wareham
  109. Institute of Medical Information Science, Biometry and Epidemiology, Ludwig-Maximilians-Universität München, München, Germany.

    • H-Erich Wichmann
  110. Department of Cardiovascular Surgery, University of Leicester, Leicester, UK.

    • Benjamin J Wright
  111. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    • Shu Ye
  112. INSERM UMRS 937, Pierre and Marie Curie University, Université Pierre et Marie Curie (UPMC)-Paris 6, Faculté de Médecine Pierre et Marie Curie, Paris, France.

    • Francois Cambien
  113. Synlab Center of Laboratory Diagnostics Heidelberg, Heidelberg, Germany.

    • Winfried März
  114. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.

    • Winfried März
  115. Institute of Public Health, Social and Preventive Medicine, Medical Faculty Manneim, University of Heidelberg, Heidelberg, Germany.

    • Winfried März
  116. Department of Haematology, University of Cambridge and NHS Blood and Transplant, Cambridge, UK.

    • Willem H Ouwehand
  117. Department of Health Sciences, University of Leicester, Leicester, UK.

    • John R Thompson
  118. Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

    • Ruth McPherson
  119. A full list of members is provided in the Supplementary Note.

    • the CARDIoGRAM Consortium

Consortia

  1. the CARDIoGRAM Consortium

    • Nilesh J Samani

Contributions

Manuscript writing: H.S., I.R.K., S.K., M.P.R., T.L.A., H.H., A.F.R.S., P. Deloukas, R.R., R.M., J.E., N.J.S.

GWAS meta-analysis samples, genotyping and analysis: H.S., I.R.K., S.K., M.P.R., T.L.A., H.H., M.P., A.F.R.S., M.B., C.G., D. Absher, D. Ardissino, K.A., S.G.B., A.J.B., J.C.B., E.B., P.S.B., M.S.B., L.C., A. Deghan, S.D., P. Diemert, J.D., A. Doering, N.E.E.M., R.E., S.E., M.F., A.R.F., S.G., J.R.G., E.H., A.H., T.I., C.I., M.A.K., J.W.K., A.K., R.L., M.L., W.L., C.L., C.M., T. Meitinger, O.M., V.M., K.M., T. Morgan, J.N., C.P.N., A.P., L.Q., D.J.R., V.S., A. Schäfer, A. Schillert, S.S., J.S., S.M.S., D.S.S., K.S., G. Thorgeirsson, G. Thorleifsson, M.T., A.G.U., B.F.V., G.A.W., H.E.W., C.W., P.S.W., J.C.M.W., B.J.W., T.Z., A.Z., F.C., L.A.C., T.Q., W.M., C.H., S.B., A.S.H., P.D., U.T., R.R., J.R.T., C.J.O., R.M., J.E., N.J.S.

Replication phase samples, genotyping and analysis: H.S., I.R.K., S.K., M.P.R., H.H., M.P., H.A., S.A., K.A., T.L.A., J.L.A., D. Ardissino, D. Absher, T.A.B., L.C.B, D.M.B., K.B., S.M.B., M.J.B., I.B., J.F.C., R.W.D., G.D., R.D., S.G.E., J.C.E., U.d.F., B.G., D.G., V.G., N.H., S.L.H., B.D.H., C.I., G.T.J., J.W.J., L.M.K., J.W.K., J.J.P.K., K.-T.K., G.K., D.L., K.L., P.L.-N., A.J.L., P.M.M., N.M., P.P.M., P.A.M., T. Morgan, T. Meitinger, T.W.M., J.B.M., S.C., M.M.N., O.O., F.P., R.S.P., C.C.P., A.A.Q., L.S.R., F.R.R., D.R., M.L.S., M.S.S., S. Sivapalaratnam, T.B.S., J.D.S., N.S., J.A.S., T.Q., K. Stark, K. Stirrups, M. Stoll, W.H.W.T., A.M.v.R., N.J.W., S.Y., P.D., U.T., R.R., R.M., J.E., N.J.S.

Analysis group: I.R.K., M.P., D. Absher, L.C., E.H., M.L., K.M., A. Schillert, G. Thorleifsson, B.F.V., G.A.W., L.A.C., J.R.T.

Biological analyses: H.S., T.L.A., H.H., M.B., C.G., Z.A., P.S.B., V.C., J.F., S.G., P.L.-N., G.L., S.M., C.R., E.S., M.T., F.C., A.H.G., T.Q., C.H., W.H.O., P.D., U.T., J.E., N.J.S.

CARDIoGRAM consortium executive group: H.S., S.K., M.P.R., J.E., N.J.S.

CARDIoGRAM consortium steering group: H.S., I.R.K., S.K., M.P.R., T.L.A., E.B., R.L., A.Z., C.H., A.S.H., U.T., J.R.T., R.M., J.E., N.J.S.

Competing financial interests

Genotyping of PennCATH and Medstar was supported by GlaxoSmithKline. D.M.W., M.C.W. and V.M. are employees of GlaxoSmithKline. H.H., S.G., J.R.G., A.K., K.S., G.T. and U.T. are employees of and/or own stock or stock options in deCODE genetics.

Corresponding authors

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Supplementary information

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  1. Supplementary Text and Figures (6M)

    Supplementary Figures 1–4, Supplementary Tables 1–14 and Supplementary Note.

Additional data