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

Nature Genetics volume 47, pages 1121–1130 (2015)Cite this article

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Abstract

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. 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. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.

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Figure 1: Comparing the 1000 Genomes Project and HapMap imputation training sets.
Figure 2: A circular Manhattan plot summarizing the 1000 Genomes Project CAD association results.
Figure 3: The imputation quality and effect size of lead variants at 46 genome-wide significant loci.
Figure 4: Regional association plots for newly identified loci associated with CAD.

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  • 14 September 2015

    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

  • Majid Nikpay
  • , Anuj Goel
  • , Hong-Hee Won
  • , Leanne M Hall
  • , Christina Willenborg
  • , Stavroula Kanoni
  • , Danish Saleheen
  • , Theodosios Kyriakou
  • , Christopher P Nelson
  • , Jemma C Hopewell
  • , Thomas R Webb
  • , Lingyao Zeng
  • , Abbas Dehghan
  • , Maris Alver
  • , Sebastian M Armasu
  • , Kirsi Auro
  • , Andrew Bjonnes
  • , Daniel I Chasman
  • , Shufeng Chen
  • , Ian Ford
  • , Nora Franceschini
  • , Christian Gieger
  • , Christopher Grace
  • , Stefan Gustafsson
  • , Jie Huang
  • , Shih-Jen Hwang
  • , Yun Kyoung Kim
  • , Marcus E Kleber
  • , King Wai Lau
  • , Xiangfeng Lu
  • , Yingchang Lu
  • , Leo-Pekka Lyytikäinen
  • , Evelin Mihailov
  • , Alanna C Morrison
  • , Natalia Pervjakova
  • , Liming Qu
  • , Lynda M Rose
  • , Elias Salfati
  • , Richa Saxena
  • , Markus Scholz
  • , Albert V Smith
  • , Emmi Tikkanen
  • , Andre Uitterlinden
  • , Xueli Yang
  • , Weihua Zhang
  • , Wei Zhao
  • , Mariza de Andrade
  • , Paul S de Vries
  • , Natalie R van Zuydam
  • , Sonia S Anand
  • , Lars Bertram
  • , Frank Beutner
  • , George Dedoussis
  • , Philippe Frossard
  • , Dominique Gauguier
  • , Alison H Goodall
  • , Omri Gottesman
  • , Marc Haber
  • , Bok-Ghee Han
  • , Jianfeng Huang
  • , Shapour Jalilzadeh
  • , Thorsten Kessler
  • , Inke R König
  • , Lars Lannfelt
  • , Wolfgang Lieb
  • , Lars Lind
  • , Cecilia M Lindgren
  • , Marja-Liisa Lokki
  • , Patrik K Magnusson
  • , Nadeem H Mallick
  • , Narinder Mehra
  • , Thomas Meitinger
  • , Fazal-ur-Rehman Memon
  • , Andrew P Morris
  • , Markku S Nieminen
  • , Nancy L Pedersen
  • , Annette Peters
  • , Loukianos S Rallidis
  • , Asif Rasheed
  • , Maria Samuel
  • , Svati H Shah
  • , Juha Sinisalo
  • , Kathleen E Stirrups
  • , Stella Trompet
  • , Laiyuan Wang
  • , Khan S Zaman
  • , Diego Ardissino
  • , Eric Boerwinkle
  • , Ingrid B Borecki
  • , Erwin P Bottinger
  • , Julie E Buring
  • , John C Chambers
  • , Rory Collins
  • , L Adrienne Cupples
  • , John Danesh
  • , Ilja Demuth
  • , Roberto Elosua
  • , Stephen E Epstein
  • , Tõnu Esko
  • , Mary F Feitosa
  • , Oscar H Franco
  • , Maria Grazia Franzosi
  • , Christopher B Granger
  • , Dongfeng Gu
  • , Vilmundur Gudnason
  • , Alistair S Hall
  • , Anders Hamsten
  • , Tamara B Harris
  • , Stanley L Hazen
  • , Christian Hengstenberg
  • , Albert Hofman
  • , Erik Ingelsson
  • , Carlos Iribarren
  • , J Wouter Jukema
  • , Pekka J Karhunen
  • , Bong-Jo Kim
  • , Jaspal S Kooner
  • , Iftikhar J Kullo
  • , Terho Lehtimäki
  • , Ruth J F Loos
  • , Olle Melander
  • , Andres Metspalu
  • , Winfried März
  • , Colin N Palmer
  • , Markus Perola
  • , Thomas Quertermous
  • , Daniel J Rader
  • , Paul M Ridker
  • , Samuli Ripatti
  • , Robert Roberts
  • , Veikko Salomaa
  • , Dharambir K Sanghera
  • , Stephen M Schwartz
  • , Udo Seedorf
  • , Alexandre F Stewart
  • , David J Stott
  • , Joachim Thiery
  • , Pierre A Zalloua
  • , Christopher J O'Donnell
  • , Muredach P Reilly
  • , Themistocles L Assimes
  • , John R Thompson
  • , Jeanette Erdmann
  • , Robert Clarke
  • , Hugh Watkins
  • , Sekar Kathiresan
  • , Ruth McPherson
  • , Panos Deloukas
  • , Heribert Schunkert
  • , Nilesh J Samani
  •  & Martin Farrall

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 to Hugh 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

Supplementary Text and Figures

Supplementary Figures 1–7 and Supplementary Note. (PDF 2221 kb)

Supplementary Tables 1–15 (XLSX 101 kb)

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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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