A comprehensive 1000 Genomes–based genome-wide association meta-analysis of coronary artery disease (original) (raw)

Change history

In the version of this article initially published online, there was a typographical error in the third sentence of the abstract. The corrected sentence should read: "In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls." The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We sincerely thank the participants and the medical, nursing, technical and administrative staff in each of the studies who have contributed to this project. We are grateful for support from our funders; more detailed acknowledgments are included in the Supplementary Note.

Author information

Author notes

  1. Majid Nikpay, Anuj Goel, Hong-Hee Won, Leanne M Hall, Christina Willenborg, Stavroula Kanoni and Danish Saleheen: These authors contributed equally to this work.
  2. Hugh Watkins, Sekar Kathiresan, Ruth McPherson, Panos Deloukas, Heribert Schunkert, Nilesh J Samani and Martin Farrall: These authors jointly supervised this work.

Authors and Affiliations

  1. Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
    Majid Nikpay, Alexandre F Stewart & Ruth McPherson
  2. Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
    Anuj Goel, Theodosios Kyriakou, Christopher Grace, Shapour Jalilzadeh, Hugh Watkins & Martin Farrall
  3. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
    Anuj Goel, Theodosios Kyriakou, Christopher Grace, Natalie R van Zuydam, Shapour Jalilzadeh, Cecilia M Lindgren, Andrew P Morris, Erik Ingelsson, Hugh Watkins & Martin Farrall
  4. Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA
    Hong-Hee Won, Andrew Bjonnes, Richa Saxena, Cecilia M Lindgren, Tõnu Esko & Sekar Kathiresan
  5. Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA
    Hong-Hee Won & Sekar Kathiresan
  6. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA
    Hong-Hee Won, Andrew Bjonnes, Richa Saxena & Sekar Kathiresan
  7. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
    Hong-Hee Won & Sekar Kathiresan
  8. Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
    Leanne M Hall, Christopher P Nelson, Thomas R Webb & Nilesh J Samani
  9. Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany
    Christina Willenborg & Jeanette Erdmann
  10. DZHK (German Research Center for Cardiovascular Research), partner site Hamburg-Lübeck-Kiel, Lübeck, Germany
    Christina Willenborg, Inke R König & Jeanette Erdmann
  11. William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
    Stavroula Kanoni, Kathleen E Stirrups & Panos Deloukas
  12. Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    Danish Saleheen & Wei Zhao
  13. Center for Non-Communicable Diseases, Karachi, Pakistan
    Danish Saleheen, Philippe Frossard, Asif Rasheed & Maria Samuel
  14. National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK
    Christopher P Nelson, Thomas R Webb, Alison H Goodall & Nilesh J Samani
  15. Nuffield Department of Population Health, Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK
    Jemma C Hopewell, King Wai Lau, Rory Collins & Robert Clarke
  16. Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
    Lingyao Zeng, Thorsten Kessler, Christian Hengstenberg & Heribert Schunkert
  17. DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
    Lingyao Zeng, Christian Gieger, Thomas Meitinger, Annette Peters, Christian Hengstenberg & Heribert Schunkert
  18. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
    Abbas Dehghan, Andre Uitterlinden, Paul S de Vries, Oscar H Franco & Albert Hofman
  19. Estonian Genome Center, University of Tartu, Tartu, Estonia
    Maris Alver, Evelin Mihailov, Natalia Pervjakova, Tõnu Esko, Andres Metspalu & Markus Perola
  20. Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
    Maris Alver & Andres Metspalu
  21. Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
    Sebastian M Armasu & Mariza de Andrade
  22. Department of Health, National Institute for Health and Welfare, Helsinki, Finland
    Kirsi Auro, Natalia Pervjakova & Markus Perola
  23. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
    Kirsi Auro, Natalia Pervjakova, Emmi Tikkanen, Markus Perola & Samuli Ripatti
  24. Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland
    Kirsi Auro, Natalia Pervjakova & Markus Perola
  25. Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
    Daniel I Chasman, Lynda M Rose, Julie E Buring & Paul M Ridker
  26. Harvard Medical School, Boston, Massachusetts, USA
    Daniel I Chasman & Paul M Ridker
  27. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
    Shufeng Chen, Xiangfeng Lu, Xueli Yang, Laiyuan Wang & Dongfeng Gu
  28. Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK
    Ian Ford
  29. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA
    Nora Franceschini
  30. Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany
    Christian Gieger & Annette Peters
  31. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany
    Christian Gieger
  32. Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala, Sweden
    Stefan Gustafsson & Erik Ingelsson
  33. Science for Life Laboratory, Uppsala University, Uppsala, Sweden
    Stefan Gustafsson & Erik Ingelsson
  34. Wellcome Trust Sanger Institute, Hinxton, UK
    Jie Huang, John Danesh & Samuli Ripatti
  35. National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA
    Shih-Jen Hwang, L Adrienne Cupples & Christopher J O'Donnell
  36. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA
    Shih-Jen Hwang & L Adrienne Cupples
  37. Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do, Korea
    Yun Kyoung Kim, Bok-Ghee Han & Bong-Jo Kim
  38. Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany
    Marcus E Kleber & Winfried März
  39. Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
    Yingchang Lu, Omri Gottesman, Erwin P Bottinger & Ruth J F Loos
  40. Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA
    Yingchang Lu & Ruth J F Loos
  41. Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
    Leo-Pekka Lyytikäinen, Pekka J Karhunen & Terho Lehtimäki
  42. Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland
    Leo-Pekka Lyytikäinen & Terho Lehtimäki
  43. Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA
    Alanna C Morrison & Eric Boerwinkle
  44. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    Liming Qu
  45. Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, California, USA
    Elias Salfati, Erik Ingelsson, Thomas Quertermous & Themistocles L Assimes
  46. Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
    Richa Saxena
  47. Institute for Medical Informatics, Statistics and Epidemiology, Medical Faculty, University of Leipzig, Leipzig, Germany
    Markus Scholz
  48. LIFE Research Center of Civilization Diseases, Leipzig, Germany
    Markus Scholz, Frank Beutner & Joachim Thiery
  49. Icelandic Heart Association, Kopavogur, Iceland
    Albert V Smith & Vilmundur Gudnason
  50. Faculty of Medicine, University of Iceland, Reykjavik, Iceland
    Albert V Smith & Vilmundur Gudnason
  51. Department of Public Health, University of Helsinki, Helsinki, Finland
    Emmi Tikkanen & Samuli Ripatti
  52. Department of Epidemiology and Biostatistics, Imperial College London, London, UK
    Weihua Zhang & John C Chambers
  53. Department of Cardiology, Ealing Hospital National Health Service (NHS) Trust, Middlesex, UK
    Weihua Zhang, John C Chambers & Jaspal S Kooner
  54. Medical Research Institute, University of Dundee, Dundee, UK
    Natalie R van Zuydam & Colin N Palmer
  55. Department of Medicine, Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada
    Sonia S Anand
  56. Platform for Genome Analytics, Institutes of Neurogenetics and Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany
    Lars Bertram
  57. Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, UK
    Lars Bertram
  58. Heart Center Leipzig, Cardiology, University of Leipzig, Leipzig, Germany
    Frank Beutner
  59. Department of Dietetics-Nutrition, Harokopio University, Athens, Greece
    George Dedoussis
  60. INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France
    Dominique Gauguier
  61. Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK
    Alison H Goodall
  62. School of Medicine, Lebanese American University, Beirut, Lebanon
    Marc Haber & Pierre A Zalloua
  63. Hypertension Division, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
    Jianfeng Huang
  64. Klinikum Rechts der Isar, Munich, Germany
    Thorsten Kessler
  65. Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany
    Inke R König
  66. Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden
    Lars Lannfelt
  67. Institut für Epidemiologie, Christian Albrechts Universität zu Kiel, Kiel, Germany
    Wolfgang Lieb
  68. Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden
    Lars Lind
  69. Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland
    Marja-Liisa Lokki
  70. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
    Patrik K Magnusson & Nancy L Pedersen
  71. Punjab Institute of Cardiology, Lahore, Pakistan
    Nadeem H Mallick
  72. All India Institute of Medical Sciences, New Delhi, India
    Narinder Mehra
  73. Institut für Humangenetik, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany
    Thomas Meitinger
  74. Institute of Human Genetics, Technische Universität München, Munich, Germany
    Thomas Meitinger
  75. Red Crescent Institute of Cardiology, Hyderabad, Pakistan
    Fazal-ur-Rehman Memon & Asif Rasheed
  76. Department of Biostatistics, University of Liverpool, Liverpool, UK
    Andrew P Morris
  77. Department of Cardiology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
    Markku S Nieminen & Juha Sinisalo
  78. Second Department of Cardiology, Attikon Hospital, School of Medicine, University of Athens, Athens, Greece
    Loukianos S Rallidis
  79. Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
    Svati H Shah & Christopher B Granger
  80. Department of Haematology, University of Cambridge, Cambridge, UK
    Kathleen E Stirrups
  81. Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
    Stella Trompet & J Wouter Jukema
  82. Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands
    Stella Trompet
  83. National Human Genome Center at Beijing, Beijing, China
    Laiyuan Wang
  84. National Institute of Cardiovascular Diseases, Karachi, Pakistan
    Khan S Zaman
  85. Division of Cardiology, Azienda Ospedaliero Universitaria di Parma, Parma, Italy
    Diego Ardissino
  86. Associazione per lo Studio della Trombosi in Cardiologia, Pavia, Italy
    Diego Ardissino
  87. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA
    Eric Boerwinkle
  88. Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA
    Ingrid B Borecki & Mary F Feitosa
  89. Imperial College Healthcare NHS Trust, London, UK
    John C Chambers & Jaspal S Kooner
  90. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
    John Danesh
  91. Berlin Aging Study II,
    Ilja Demuth
  92. Research Group on Geriatrics, Charité Universitätsmedizin Berlin, Berlin, Germany
    Ilja Demuth
  93. Institute of Medical and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany
    Ilja Demuth
  94. Grupo de Epidemiología y Genética Cardiovascular, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain
    Roberto Elosua
  95. MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC, USA
    Stephen E Epstein
  96. Division of Endocrinology and Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA
    Tõnu Esko
  97. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA
    Tõnu Esko
  98. Department of Cardiovascular Research, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
    Maria Grazia Franzosi
  99. Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK
    Alistair S Hall
  100. Department of Medicine Solna, Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Karolinska Institutet, Stockholm, Sweden
    Anders Hamsten
  101. Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA
    Tamara B Harris
  102. Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA
    Stanley L Hazen
  103. Kaiser Permanente Division of Research, Oakland, California, USA
    Carlos Iribarren
  104. Durrer Center for Cardiogenetic Research, Amsterdam, the Netherlands
    J Wouter Jukema
  105. Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands
    J Wouter Jukema
  106. Department of Forensic Medicine, University of Tampere School of Medicine, Tampere, Finland
    Pekka J Karhunen
  107. Cardiovascular Science, National Heart and Lung Institute, Imperial College London, London, UK
    Jaspal S Kooner
  108. Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
    Iftikhar J Kullo
  109. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
    Ruth J F Loos
  110. Department of Clinical Sciences, Hypertension and Cardiovascular Disease, Lund University, University Hospital Malmö, Malmö, Sweden
    Olle Melander
  111. Synlab Academy, Synlab Services, Mannheim, Germany
    Winfried März
  112. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
    Winfried März
  113. Stanford Cardiovascular Institute, Stanford University, Stanford, California, USA
    Thomas Quertermous & Themistocles L Assimes
  114. Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
    Daniel J Rader
  115. Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
    Daniel J Rader & Muredach P Reilly
  116. University of Ottawa Heart Institute, Ottawa, Ontario, Canada
    Robert Roberts
  117. Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
    Veikko Salomaa
  118. Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
    Dharambir K Sanghera
  119. Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
    Dharambir K Sanghera
  120. Oklahoma Center for Neuroscience, Oklahoma City, Oklahoma, USA
    Dharambir K Sanghera
  121. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
    Stephen M Schwartz
  122. Department of Epidemiology, University of Washington, Seattle, Washington, USA
    Stephen M Schwartz
  123. Department of Prosthetic Dentistry, Center for Dental and Oral Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Udo Seedorf
  124. Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, UK
    David J Stott
  125. Institute for Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Medical Faculty, Leipzig, Germany
    Joachim Thiery
  126. Harvard School of Public Health, Boston, Massachusetts, USA
    Pierre A Zalloua
  127. and Blood Institute Division of Intramural Research, National Heart, Lung, Bethesda, Maryland, USA
    Christopher J O'Donnell
  128. Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA
    Christopher J O'Donnell
  129. Department of Health Sciences, University of Leicester, Leicester, UK
    John R Thompson
  130. Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia
    Panos Deloukas

Consortia

the CARDIoGRAMplusC4D Consortium

Contributions

Cohort oversight: D.A., E.B., I.B.B., E.P.B., J.E.B., J.C.C., R. Collins, L.A.C., J.D., I.D., R.E., S.E.E., T.E., M.F.F., O.H.F., M.G.F., C.B.G., D. Gu, V.G., A.S.H., A. Hamsten, T.B.H., S.L.H., C.H., A. Hofman, E.I., C.I., J.W.J., P.J.K., B.-J.K., J.S.K., I.J.K., T.L., R.J.F.L., O.M., A.M., W.M., C.N.P., M.P., T.Q., D.J.R., P.M.R., S.R., R.R., V.S., D.K.S., S.M.S., U.S., A.F.S., D.J.S., J.T., P.A.Z., C.J.O'D., M.P.R., T.L.A., J.R.T., J.E., H.W., S. Kathiresan, R.M., P.D., H.S., N.J.S. and M.F. Cohort genotyping: H.-H.W., S. Kanoni, D.S., J.C.H., Jie Huang, M.E.K., Y.L., L.-P.L., A.U., S.S.A., L.B., G.D., D. Gauguier, A.H.G., M.H., B.-G.H., S.J., L. Lind, C.M.L., M.-L.L., P.K.M., A.P.M., M.S.N., N.L.P., J.S., K.E.S., S.T., L.W., I.B.B., J.C.C., R. Collins, M.F.F., A. Hofman, E.I., J.S.K., T.L., R.R., D.K.S., A.F.S., R. Clarke, P.D. and N.J.S. Cohort phenotyping: D.S., J.C.H., A.D., M.A., K.A., Y.K.K., E.M., L.M.R., S.S.A., F.B., G.D., P.F., A.H.G., O.G., Jianfeng Huang, T. Kessler, I.R.K., L. Lannfelt, W.L., L. Lind, C.M.L., P.K.M., N.H.M., N.M., T.M., F.-ur-R.M., A.P.M., N.L.P., A.P., L.S.R., A.R., M. Samuel, S.H.S., K.S.Z., D.A., J.E.B., J.C.C., R. Collins, R.E., C.B.G., V.G., A.S.H., A. Hamsten, S.L.H., E.I., J.W.J., P.J.K., J.S.K., I.J.K., O.M., A.M., M.P., R.R., D.K.S., A.F.S., D.J.S., P.A.Z., M.P.R., R. Clarke, S. Kathiresan, H.S. and N.J.S. Cohort data analyst: M.N., A.G., H.-H.W., L.M.H., C.W., S. Kanoni, D.S., T. Kyriakou, C.P.N., J.C.H., T.R.W., L.Z., A.D., M.A., S.M.A., K.A., A.B., D.I.C., S.C., I.F., N.F., C. Gieger, C. Grace, S.G., Jie Huang, S.-J.H., Y.K.K., M.E.K., K.W.L., X.L., Y.L., L.-P.L., E.M., A.C.M., N.P., L.Q., L.M.R., E.S., R.S., M. Scholz, A.V.S., E.T., A.U., X.Y., W. Zhang, W. Zhao, M.d.A., P.S.d.V., N.R.v.Z., M.F.F., J.R.T. and M.F. Meta-analysis: M.N., A.G., H.-H.W., L.M.H., C.P.N., J.R.T. and M.F. Variant annotation: M.N., A.G., H.-H.W., T. Kyriakou, J.C.H. and T.R.W. Manuscript drafting: M.N., A.G., H.-H.W., L.M.H., T. Kyriakou, J.C.H., H.W., S. Kathiresan, R.M., H.S., N.J.S. and M.F. Project steering committee: M.N., A.G., H.-H.W., L.M.H., S. Kanoni., J.C.H., D.I.C., M.E.K., N.R.v.Z., C.N.P., R.R., C.J.O'D., M.P.R., T.L.A., J.R.T., J.E., R. Clarke, H.W., S. Kathiresan, R.M., P.D., H.S., N.J.S. and M.F. (secretariat: J.C.H. and R. Clarke). CARDIoGRAMplusC4D executive committee: J.D., D. Gu, A. Hamsten, J.S.K., R.R., H.W., S. Kathiresan, P.D., H.S. and N.J.S.

Corresponding authors

Correspondence toHugh Watkins, Sekar Kathiresan, Ruth McPherson or Martin Farrall.

Ethics declarations

Competing interests

The author declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Venn diagram showing case-control overlap between 1000G GWAS and Metabochip studies.

Venn diagram showing the number of cases (top) and controls (bottom) that overlap between the present 1000G GWAS meta-analysis study and the Metabochip study (Nat. Genet. 45, 25–33, 2013). There is a 57.5% overlap of our cases and a 40.1% overlap of our controls with the previously published study.

Supplementary Figure 2 A Manhattan plot summarizing the 1000 Genomes CAD additive association results.

The meta-analysis statistics have been adjusted for overdispersion (genomic control parameter = 1.18) and have been capped to P = 1 × 10−20. The genome-wide significance threshold is shown as a horizontal blue line at P < 5 × 10−8. Novel CAD loci are presented with red stacks and gene names (Table 1). Previously reported loci showing genome-wide significance are shown in brown, and those showing nominal significance (P < 0.05) in our meta-analysis are shown in blue (Supplementary Table 2).

Supplementary Figure 3 Comparing effect sizes for the MI subphenotype and the inclusive CAD phenotype.

Point estimates of effect sizes (odds ratios) are shown by open circles, with 95% confidence intervals represented by solid lines. The line of identity is shown as a dashed line. Loci showing marked differences in effect sizes are shown in blue.

Supplementary Figure 4 Heat map of the number of variants with power >90% to detect genome-wide significant association.

Heat map summarizing the number of variants that were calculated to be powered at ≥90% in the meta-analysis to detect a genome-wide significant association with an additive susceptibility variant with odds ratio (OR) = 1.3. Each cell is shaded from white to black to represent larger and smaller numbers of variants, respectively. The modal cell covers variants in the sector with 0.05 < MAF < 0.075 and imputation quality >0.95.

Source data

Supplementary Figure 5 Allele frequency analysis to identify strand flipping and data formatting issues.

Allele frequency analysis to identify systematic allele mismatching in individual studies due to strand flipping and other data formatting issues. (a) Proportion of variants that align with the 1000 Genomes phase 1 v3 training set minor allele after assignment to bins on the basis of MAF. The blue plot shows a typical analysis for studies with well-matched alleles, such that there is 100% concordance for lower-frequency alleles (MAF < 0.2) that declines to 50% for more frequent alleles. The red trace for study TH (Supplementary Table 1 of studies with study code) shows a marked discordance in allele frequencies that was resolved before inclusion in the meta-analysis. (b) Surface plot of 28 studies with 2 studies showing systematic strand flipping and further studies showing more subtly different allele frequency patterns. (c) Allele frequency analysis for data submitted to the meta-analysis (i.e., after any systematic mismatching issues had been resolved). Six studies of East and South Asian, Hispanic and African-American ancestries show MAF distortions that contrast with those of the remaining 42 European-ancestry studies.

Supplementary Figure 6 Quantile-quantile plots of the double–genomic controlled CAD meta-analysis results.

Shaded areas represent 95% confidence intervals. (a,b) Plots showing all additive and recessive results. (c,d) Plots showing additive and recessive results after removing variants from known loci. Supplementary Table 15 refers to the genomic control correction of each study before the final meta-analysis.

Supplementary Figure 7 Comparison of GCTA joint association analysis with standard multiple–logistic regression analysis in four studies.

We have investigated the accuracy of the GCTA joint association analysis by comparing the approximate GCTA results with a standard multiple–logistic regression analysis in 4 studies (MIGEN, PROCARDIS, OHGS and Interheart) for the 202 FDR variants. The figure shows scatterplots of the regression coefficients (left column), standard errors (center column) and –log10 (P values) (right column) for each variant; for each scatterplot, the x axis shows the standard multiple–logistic regression result, and the y axis shows the corresponding GCTA COJO result. The regression coefficients and standard errors for the majority (95%) of the variants are very accurately approximated as their results lie close to the line of identity (y = x) shown in red. The –log10 (P values) for the two analyses were positively correlated (0.86 < ρ < 0.93).

Supplementary information

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the CARDIoGRAMplusC4D Consortium. A comprehensive 1000 Genomes–based genome-wide association meta-analysis of coronary artery disease.Nat Genet 47, 1121–1130 (2015). https://doi.org/10.1038/ng.3396

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