Article | Published:

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

Nature Genetics volume 45, pages 2533 (2013) | Download Citation

Abstract

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r2 < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. Lifetime risks of cardiovascular disease. N. Engl. J. Med. 366, 321–329 (2012).

  2. 2.

    & Thirty-five common variants for coronary artery disease: the fruits of much collaborative labour. Hum. Mol. Genet. 20 R2, R198–R205 (2011).

  3. 3.

    , , , & Genome-wide association studies: progress and potential for drug discovery and development. Nat. Rev. Drug Discov. 7, 221–230 (2008).

  4. 4.

    et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N. Engl. J. Med. 366, 1108–1118 (2012).

  5. 5.

    et al. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat. Genet. 43, 333–338 (2011).

  6. 6.

    Coronary Artery Disease (C4D) Genetics Consortium. A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease. Nat. Genet. 43, 339–344 (2011).

  7. 7.

    et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N. Engl. J. Med. 361, 2518–2528 (2009).

  8. 8.

    et al. Genomewide association analysis of coronary artery disease. N. Engl. J. Med. 357, 443–453 (2007).

  9. 9.

    et al. New susceptibility locus for coronary artery disease on chromosome 3q22.3. Nat. Genet. 41, 280–282 (2009).

  10. 10.

    et al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat. Genet. 41, 334–341 (2009).

  11. 11.

    et al. A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nat. Genet. 41, 1182–1190 (2009).

  12. 12.

    et al. Genome-wide association identifies a susceptibility locus for coronary artery disease in the Chinese Han population. Nat. Genet. 43, 345–349 (2011).

  13. 13.

    The IBC 50K CAD Consortium. Large-scale gene-centric analysis identifies novel variants for coronary artery disease. PLoS Genet. 7, e1002260 (2011).

  14. 14.

    et al. Genome partitioning of genetic variation for complex traits using common SNPs. Nat. Genet. 43, 519–525 (2011).

  15. 15.

    et al. The Metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits. PLoS Genet. 8, e1002793 (2012).

  16. 16.

    et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–713 (2010).

  17. 17.

    International Consortium for Blood Pressure Genome-Wide Association Studies. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478, 103–109 (2011).

  18. 18.

    et al. Twelve type 2 diabetes susceptibility loci identified through large scale association analysis. Nat. Genet. 42, 579–589 (2010).

  19. 19.

    et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat. Genet. 42, 105–116 (2010).

  20. 20.

    et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat. Genet. 42, 937–948 (2010).

  21. 21.

    et al. Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits. Nat. Genet. 44, 369–375 (2012).

  22. 22.

    , , & APOE/C1/C4/C2 gene cluster genotypes, haplotypes and lipid levels in prospective coronary heart disease risk among UK healthy men. Mol. Med. 16, 389–399 (2010).

  23. 23.

    et al. Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies. Lancet 377, 383–392 (2011).

  24. 24.

    et al. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat. Genet. 42, 949–960 (2010).

  25. 25.

    & Statistical methods for identifying differentially expressed genes in DNA microarrays. Methods Mol. Biol. 224, 149–157 (2003).

  26. 26.

    , , & Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ. Res. 91, 281–291 (2002).

  27. 27.

    Emerging Risk Factors Collaboration. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N. Engl. J. Med. 364, 829–841 (2011).

  28. 28.

    et al. Incidence of new-onset diabetes and impaired fasting glucose in patients with recent myocardial infarction and the effect of clinical and lifestyle risk factors. Lancet 370, 667–675 (2007).

  29. 29.

    et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 52, 2288–2298 (2009).

  30. 30.

    Atherosclerosis is an inflammatory disease. Am. Heart J. 138, S419–S420 (1999).

  31. 31.

    et al. Association of genetic risk variants with expression of proximal genes identifies novel susceptibility genes for cardiovascular disease. Circ. Cardiovasc. Genet. 3, 365–373 (2010).

  32. 32.

    et al. Mapping cis- and trans-regulatory effects across multiple tissues in twins: the MuTHER Study. Nat. Genet. 44, 1084–1089 (2012).

  33. 33.

    et al. Mapping the genetic architecture of gene expression in human liver. PLoS Biol. 6, e107 (2008).

  34. 34.

    et al. Global patterns of cis variation in human cells revealed by high-density allelic expression analysis. Nat. Genet. 41, 1216–1222 (2009).

Download references

Acknowledgements

We thank the personnel of the Wellcome Trust Sanger Institute (WTSI) Genotyping Facility, in particular S. Edkins, for supervising the genotyping of the AMC-PAS, Cardiogenics, GLACIER, MORGAM, PROMIS, THISEAS, and WTCCC cohorts.

AMC-PAS/SANQUIN.

We thank A.A. Soussan for technical assistance.

We thank personnel from the Estonian Genome Center of the University of Tartu (EGCUT) and the Estonian Biocentre, especially M. Hass and V. Soo, for data generation.

FINCAVAS.

We thank the staff of the Department of Clinical Physiology for collecting the exercise test data.

The GLACIER Study.

The GLACIER study is a nested study within the Northern Sweden Health and Disease Study; phenotyping was conducted as part of the Västerbotten Intervention Project. We thank the participants and the investigators from these studies for their valuable contributions, with specific thanks to L. Weinehall, Å. Agren, K. Enquist and T. Johansson.

GoDARTS Dundee.

We are grateful to all the participants who took part in this study, to the general practitioners, to the Scottish School of Primary Care for their help in recruiting the participants and to the whole team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. We acknowledge the support of the Health Informatics Centre at the University of Dundee in managing and supplying the anonymized data and National Health Service (NHS) Tayside, the original data owner.

Heart Protection Study.

The study was designed and conducted by the Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU) at the University of Oxford. Genotyping was supported by a grant to Oxford University and Centre National de Genotypage (CNG) from Merck. The funders had no role in the design of the study or in the data collection or analysis. We especially acknowledge the participants in the study, the Steering Committee and our collaborators. J.C.H. acknowledges support from the British Heart Foundation (BHF) Centre of Research Excellence.

LOLIPOP.

We thank the participants and research staff who made the study possible.

MORGAM study.

We thank the contributing sites and key personnel, as detailed below.

Finland: We thank FINRISK, National Institute for Health and Welfare, Helsinki: V.S. (principal investigator), A. Juolevi, E. Vartiainen and P. Jousilahti; Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study, National Institute for Health and Welfare, Helsinki: J. Virtamo (principal investigator) and H. Kilpeläinen; the MORGAM Data Centre, National Institute for Health and Welfare, Helsinki: K. Kuulasmaa (responsible person), Z. Cepaitis, A. Haukijärvi, B. Joseph, J. Karvanen, S. Kulathinal, M. Niemelä and O. Saarela; and the MORGAM Central Laboratory, National Institute for Health and Welfare, Helsinki: M.P. (responsible person), P. Laiho and M. Sauramo.

France: We thank the National Coordinating Centre, National Institute of Health and Medical Research (U258), Paris: P. Ducimetière (national coordinator) and A. Bingham; Prospective Epidemiological Study of Myocardial Infarction (PRIME)/Strasbourg, Department of Epidemiology and Public Health, EA 3430, University of Strasbourg, Faculty of Medicine, Strasbourg: D. Arveiler (principal investigator), B. Haas and A. Wagner; PRIME/Toulouse, Department of Epidemiology, Toulouse University School of Medicine, Toulouse: J.F. (principal investigator), J.-B. Ruidavets, V. Bongard, D. Deckers, C. Saulet and S. Barrere; PRIME/Lille, Department of Epidemiology and Public Health, INSERM U744–Université Lille Nord de France–Institut Pasteur de Lille, Lille: P. Amouyel (principal investigator), M. Montaye, B. Lemaire, S. Beauchant, D. Cottel, C. Graux, N. Marecaux, C. Steclebout and S. Szeremeta; and the MORGAM Laboratory, INSERM U937, Paris: F.C. (responsible person), L. Tiret and V. Nicaud.

Italy: We thank Centro Ricerche EPIMED–Epidemiologia e Medicina Preventiva, Dipartimento di Medicina Clinica e Sperimentale; Università dell' Insubria, Varese: M.M.F. (principal investigator) and G. Veronesi; and Research Centre on Public Health, University of Milano–Bicocca, Monza: G. Cesana.

UK: We thank PRIME/Belfast, Queen's University Belfast, Belfast: F.K. (principal investigator), A.E. (former principal investigator), J. Yarnell and E. Gardner; and the MORGAM Coordinating Centre, Queen's University Belfast, Belfast: A.E. (MORGAM coordinator), S. Cashman and F.K.

MORGAM management group: A.E. (chair), S.S.B., F.C., M.M.F., K. Kuulasmaa, A. Palotie, M.P., A.P., V.S., H. Tunstall-Pedoe and P.G. Wiklund. Previous members: K. Asplund, L. Peltonen, D. Shields and B. Stegmayr. The PRIME Study is organized under an agreement between INSERM and the Merck, Sharpe and Dohme-Chibret Laboratory, with the following participating laboratories: The Strasbourg MONICA Project, Laboratoire d'Epidémiologie et de Santé Publique, and the Université de Strasbourg, Strasbourg, France (D. Arveiler and B. Haas); The Toulouse MONICA Project, UMR INSERM 1027, and the Department of Epidemiology, Toulouse University School of Medicine, Université Paul Sabatier, Toulouse, France (J.F. and J.-B. Ruidavets); The Lille MONICA Project, INSERM U744, Institut Pasteur de Lille and Université Lille Nord de France, Lille, France (P. Amouyel and M. Montaye); The Department of Epidemiology and Public Health, Queen's University, Belfast, Belfast, UK (A.E., J. Yarnell and F.K.); The Department of Atherosclerosis, INSERM U545, Institut Pasteur de Lille, Faculté de Médecine and Université Lille Nord de France, Lille, France (G. Luc and J.-M. Bard); The Laboratory of Haematology, INSERM U626, and Hôpital La Timone, Marseille, France (I. Juhan-Vague and P. Morange); The Laboratory of Endocrinology, INSERM U563, Toulouse, France (B. Perret); The Vitamin Research Unit, The University of Bern, Bern, Switzerland (F. Gey); The Nutrition and Metabolism Group, Centre for Public Health, Queen's University Belfast, Belfast, UK (J. Woodside and I. Young); The DNA Bank, INSERM/Université Pierre et Marie Curie (UPMC), Paris Université Unite Mixte de Recherche (UMRS) 937, Paris (F.C.); The Coordinating Centre, Institut Fédératif de Recherche Santé Publique (IFR 69), Villejuif, France (P. Ducimetière); and INSERM U970, Villejuif, France, and University Paris V, Paris Cardiovascular Research Centre (PAARC), Paris (A. Bingham).

PIVUS/Swedish Twin Registry.

We thank the SNP&SEQ Technology Platform in Uppsala (see URLs) for genotyping, in particular T. Axelsson, A.-C. Wiman and C. Pöntinen for excellent assistance.

Ulm (EMIL).

We thank the Centre of Excellence Baden-Wuerttemberg Metabolic Disorders.

WTCCC.

We thank the BHF Family Heart Study Research Group for the collection of the cases.

Author information

Author notes

    • Panos Deloukas
    • , Stavroula Kanoni
    • , Christina Willenborg
    • , Martin Farrall
    • , Themistocles L Assimes
    • , John R Thompson
    • , Erik Ingelsson
    • , Danish Saleheen
    • , Jeanette Erdmann
    • , Muredach P Reilly
    • , Rory Collins
    • , Sekar Kathiresan
    • , Anders Hamsten
    • , Jaspal S Kooner
    • , Unnur Thorsteinsdottir
    • , John Danesh
    • , Colin N A Palmer
    • , Robert Roberts
    • , Hugh Watkins
    • , Heribert Schunkert
    •  & Nilesh J Samani

    These authors contributed equally to this work.

Affiliations

  1. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    • Panos Deloukas
    • , Stavroula Kanoni
    • , Kathleen Stirrups
    • , Inês Barroso
    • , Sarah E Hunt
    • , Cordelia Langford
    • , Tsun-Po Yang
    • , Willem H Ouwehand
    • , Manjinder S Sandhu
    •  & Samuli Ripatti
  2. Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany.

    • Christina Willenborg
    •  & Jeanette Erdmann
  3. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Martin Farrall
    • , Anuj Goel
    • , Mark I McCarthy
    • , John F Peden
    • , N William Rayner
    • , Dominique Gauguier
    •  & Hugh Watkins
  4. Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

    • Martin Farrall
    • , Jean-Baptiste Cazier
    • , Anuj Goel
    •  & Hugh Watkins
  5. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.

    • Themistocles L Assimes
    • , Benjamin A Goldstein
    • , Joshua W Knowles
    •  & Thomas Quertermous
  6. Department of Health Sciences, University of Leicester, Leicester, UK.

    • John R Thompson
  7. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Erik Ingelsson
    • , Stefan Gustafsson
    • , Ci Song
    •  & Nancy L Pedersen
  8. Center for Non-Communicable Diseases, Karachi, Pakistan.

    • Danish Saleheen
  9. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Danish Saleheen
    • , Asif Rasheed
    •  & John Danesh
  10. Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Danish Saleheen
    •  & Weang K Ho
  11. Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany.

    • Inke R König
    •  & Andreas Ziegler
  12. Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.

    • Åsa Johansson
    • , Niclas Eriksson
    • , Lars Wallentin
    •  & Agneta Siegbahn
  13. Division of Cardiovascular and Neuronal Remodelling, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK.

    • Alistair S Hall
  14. Center for Genome Science, Korea National Institute of Health, Korea Center for Disease Control and Prevention, Yeonje-ri, Chungwon-gun, Korea.

    • Jong-Young Lee
    • , Bok-Ghee Han
    •  & Ji-Young Lee
  15. Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

    • Cristen J Willer
  16. Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.

    • Cristen J Willer
  17. Department of Epidemiology and Biostatistics, Imperial College London, London, UK.

    • John C Chambers
    •  & Weihua Zhang
  18. Estonian Genome Center, University of Tartu, Tartu, Estonia.

    • Tõnu Esko
    • , Krista Fischer
    •  & Andres Metspalu
  19. Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.

    • Tõnu Esko
    • , Evelin Mihailov
    •  & Andres Metspalu
  20. Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.

    • Lasse Folkersen
    • , Rona J Strawbridge
    • , Per Eriksson
    •  & Anders Hamsten
  21. Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.

    • Lasse Folkersen
    • , Rona J Strawbridge
    • , Per Eriksson
    •  & Anders Hamsten
  22. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • Elin Grundberg
  23. Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.

    • Aki S Havulinna
    • , Kati Kristiansson
    • , Kari Kuulasmaa
    • , Veikko Salomaa
    • , Jarmo Virtamo
    •  & Markus Perola
  24. Clinical Trial Service Unit, University of Oxford, Oxford, UK.

    • Jemma C Hopewell
    • , Sarah Parish
    • , Robert Clarke
    •  & Rory Collins
  25. Epidemiological Studies Unit, University of Oxford, Oxford, UK.

    • Jemma C Hopewell
    • , Sarah Parish
    • , Robert Clarke
    •  & Rory Collins
  26. Mannheim Institute of Public Health, Social and Preventive Medicine, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany.

    • Marcus E Kleber
    •  & Winfried März
  27. Ludwigshafen Risk and Cardiovascular Health (LURIC) Study, Freiburg, Germany.

    • Marcus E Kleber
  28. Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

    • Per Lundmark
    • , Anders Lundmark
    • , Lars Lind
    •  & Ann-Christine Syvänen
  29. Department of Clinical Chemistry, Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.

    • Leo-Pekka Lyytikäinen
    •  & Terho Lehtimäki
  30. Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland.

    • Leo-Pekka Lyytikäinen
    •  & Terho Lehtimäki
  31. Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK.

    • Suzanne Rafelt
    • , Peter S Braund
    • , Alison H Goodall
    •  & Nilesh J Samani
  32. Genetic & Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University Diabetes Center, Skåne University Hospital, Malmö, Sweden.

    • Dmitry Shungin
    •  & Paul W Franks
  33. Department of Public Health & Clinical Medicine, Genetic Epidemiology & Clinical Research Group, Section for Medicine, Umeå University, Umeå, Sweden.

    • Dmitry Shungin
    •  & Paul W Franks
  34. Department of Odontology, Umeå University, Umeå, Sweden.

    • Dmitry Shungin
    •  & Paul W Franks
  35. deCODE Genetics, Reykjavik, Iceland.

    • Gudmar Thorleifsson
    • , Hilma Holm
    • , Kari Stefansson
    •  & Unnur Thorsteinsdottir
  36. Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland.

    • Emmi Tikkanen
    •  & Peter J Wagner
  37. Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.

    • Emmi Tikkanen
    • , Peter J Wagner
    •  & Samuli Ripatti
  38. Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.

    • Natalie Van Zuydam
    • , Alex S F Doney
    • , Andrew D Morris
    •  & Colin N A Palmer
  39. Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Benjamin F Voight
  40. HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.

    • Lindsay L Waite
    •  & Devin Absher
  41. Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

    • David Altshuler
    • , Ron Do
    • , Pierre Fontanillas
    •  & Sekar Kathiresan
  42. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • David Altshuler
  43. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • David Altshuler
    •  & Ron Do
  44. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • David Altshuler
  45. 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
  46. University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

    • Inês Barroso
  47. National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.

    • Peter S Braund
    • , Alison H Goodall
    •  & Nilesh J Samani
  48. Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.

    • Christof Burgdorf
    • , Thorsten Kessler
    • , Moritz P Rumpf
    •  & Heribert Schunkert
  49. Practice of Gynecology, Ulm University Medical Centre, Ulm, Germany.

    • Simone Claudi-Boehm
  50. Biotherapeutics and Bioinnovation Center, Pfizer, South San Francisco, California, USA.

    • David Cox
  51. Department of Dietetics–Nutrition, Harokopio University, Athens, Greece.

    • Maria Dimitriou
    •  & George Dedoussis
  52. Klinik für Innere Medizin, Kreiskrankenhaus Rendsburg, Rendsburg, Germany.

    • NourEddine El Mokhtari
    •  & Diana Rubin
  53. Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

    • Anders Franco-Cereceda
  54. Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

    • Bruna Gigante
    • , Karin Leander
    •  & Ulf de Faire
  55. Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmö, Malmö, Sweden.

    • Leif Groop
    •  & Olle Melander
  56. Commissariat à l′Energie Atomique (CEA)–Genomics Institute, National Genotyping Centre, Paris, France.

    • Jörg Hager
  57. Department of Public Health & Clinical Medicine, Section for Nutritional Research, Umeå University, Umeå, Sweden.

    • Göran Hallmans
  58. Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.

    • Hyun M Kang
    •  & Michael Boehnke
  59. Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.

    • Thomas Illig
    •  & Norman Klopp
  60. First Cardiology Department, Onassis Cardiac Surgery Center 356, Athens, Greece.

    • Genovefa Kolovou
  61. Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.

    • Johanna Kuusisto
    •  & Markku Laakso
  62. Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

    • Claudia Langenberg
    • , Nicholas Wareham
    •  & Manjinder S Sandhu
  63. Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.

    • Marja-Liisa Lokki
  64. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.

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

    • Mark I McCarthy
  66. Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Christa Meisinger
    •  & Annette Peters
  67. Institut National de la Santé et la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) S937, Institute for Cardiometabolism and Nutrition (ICAN), Pierre and Marie Curie (Paris 6) University, Paris, France.

    • Seraya Maouche
    • , Francois Cambien
    •  & David-Alexandre Trégouët
  68. Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.

    • Martina Müller-Nurasyid
  69. Chair of Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.

    • Martina Müller-Nurasyid
  70. Chair of Genetic Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.

    • Martina Müller-Nurasyid
  71. Institute of Genetic Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Martina Müller-Nurasyid
  72. Heart Centre, Department of Cardiology, Tampere University Hospital, Tampere, Finland.

    • Kjell Nikus
  73. Division of Endocrinology and Diabetes, Department of Internal Medicine, Ulm University Medical Centre, Ulm, Germany.

    • Silke Rosinger
    •  & Bernhard O Boehm
  74. Institut für Klinische Molekularbiologie, Christian-Albrechts Universität, Kiel, Germany.

    • Arne Schäfer
    •  & Stefan Schreiber
  75. Division of Epidemiology, Multidisciplinary Cardiovascular Research Centre (MCRC) University of Leeds, Leeds, UK.

    • Mohan Sivananthan
  76. Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK.

    • Mohan Sivananthan
  77. University of Ottawa Heart Institute, Cardiovascular Research Methods Centre Ontario, Ottawa, Ontario, Canada.

    • Alexandre F R Stewart
    • , George A Wells
    •  & Robert Roberts
  78. Ruddy Canadian Cardiovascular Genetics Centre, Ottawa, Ontario, Canada.

    • Alexandre F R Stewart
    • , George A Wells
    •  & Robert Roberts
  79. National Heart and Lung Institute (NHLI), Imperial College London, Hammersmith Hospital, London, UK.

    • Sian-Tsung Tan
    •  & Jaspal S Kooner
  80. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Gudmundur Thorgeirsson
    • , Villi Gudnason
    • , Kari Stefansson
    •  & Unnur Thorsteinsdottir
  81. Department of Medicine, Landspitali University Hospital, Reykjavik, Iceland.

    • Gudmundur Thorgeirsson
  82. Department of Experimental Immunohematology, Sanquin, Amsterdam, The Netherlands.

    • C Ellen van der Schoot
  83. Center for Thrombosis and Hemostasis, University Medical Center Mainz, Johannes Gutenberg University Mainz, Mainz, Germany.

    • Philipp S Wild
  84. Department of Medicine 2, University Medical Center Mainz, Johannes Gutenberg University Mainz, Mainz, Germany.

    • Philipp S Wild
  85. Institut Pasteur de Lille, INSERM U744, Université Lille Nord de France, Lille, France.

    • Philippe Amouyel
  86. Department of Epidemiology and Public Health, EA3430, University of Strasbourg, Strasbourg, France.

    • Dominique Arveiler
  87. Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.

    • Hanneke Basart
    •  & G Kees Hovingh
  88. Human Genetics Center, University of Texas Health Science Center, Houston, Texas, USA.

    • Eric Boerwinkle
  89. Department of Experimental Medicine, University of Milano–Bicocca, Monza, Italy.

    • Paolo Brambilla
  90. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Adrienne L Cupples
  91. National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Adrienne L Cupples
  92. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Abbas Dehghan
    •  & Christopher O'Donnell
  93. Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany.

    • Patrick Diemert
    •  & Stefan S Blankenberg
  94. Cardiovascular Research Institute, Washington Hospital Center, Washington, DC, USA.

    • Stephen E Epstein
  95. Centre for Public Health, The Queen's University of Belfast, Belfast, UK.

    • Alun Evans
  96. Research Centre for Epidemiology and Preventive Medicine (EPIMED), Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy.

    • Marco M Ferrario
  97. Department of Cardiology, Toulouse University School of Medicine, Rangueil Hospital, Toulouse, France.

    • Jean Ferrières
  98. INSERM UMR S872, Cordeliers Research Centre, Paris, France.

    • Dominique Gauguier
  99. Division of Research, Kaiser Permanente Northern California, Oakland, California, USA.

    • Alan S Go
    •  & Carlos Iribarren
  100. Icelandic Heart Association, Kopavogur, Iceland.

    • Villi Gudnason
  101. Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

    • Stanley L Hazen
  102. Cardiology Division, Department of Internal Medicine, Cardiovascular Genome Center, Yonsei University, Seoul, Korea.

    • Yangsoo Jang
  103. Department of Clinical Physiology, Tampere University Hospital and University of Tampere, Tampere, Finland.

    • Mika Kähönen
  104. UK Clinical Research Collaboration (UKCRC) Centre of Excellence for Public Health (Northern Ireland), Queen's University of Belfast, Belfast, UK.

    • Frank Kee
  105. Department of Internal Medicine, Cardiovascular Center, Seoul National University Hospital, Seoul, Korea.

    • Hyo-Soo Kim
  106. Department of Internal Medicine II–Cardiology, Ulm University Medical Center, Ulm, Germany.

    • Wolfgang Koenig
  107. Science Center, Tampere University Hospital, Tampere, Finland.

    • Wolfgang Kratzer
    •  & Reijo Laaksonen
  108. Department of Haematology, University of Cambridge, Cambridge, UK.

    • Willem H Ouwehand
  109. National Health Service (NHS) Blood and Transplant, Cambridge, UK.

    • Willem H Ouwehand
  110. Division of Cardiology, Samsung Medical Center, Seoul, Korea.

    • Jeong E Park
  111. Munich Heart Alliance, Munich, Germany.

    • Annette Peters
  112. Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Daniel J Rader
  113. Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA.

    • Eric Schadt
  114. Center for Human Genetics, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.

    • Svati H Shah
  115. Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.

    • Svati H Shah
  116. Division of Cardiology, Department of Medicine, Helsinki University Central Hospital (HUCH), Helsinki, Finland.

    • Juha Sinisalo
    •  & Markku S Nieminen
  117. Klinik und Poliklinik für Innere Medizin II, Regensburg, Germany.

    • Klaus Stark
    • , Martina E Zimmermann
    •  & Christian Hengstenberg
  118. Department of Human Genetics, McGill University, Montréal, Québec, Canada.

    • Tomi Pastinen
  119. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Paul W Franks
  120. Lebanese American University, Chouran, Beirut, Lebanon.

    • Pierre A Zalloua
  121. Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Muredach P Reilly
  122. Synlab Academy, Mannheim, Germany.

    • Winfried März
  123. Cardiology Division, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Sekar Kathiresan
  124. Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Sekar Kathiresan

Consortia

  1. The CARDIoGRAMplusC4D Consortium

  2. DIAGRAM Consortium

    A list of members and affiliations appears in the Supplementary Note.

  3. CARDIOGENICS Consortium

    A list of members and affiliations appears in the Supplementary Note.

  4. MuTHER Consortium

    A list of members and affiliations appears in the Supplementary Note.

  5. Wellcome Trust Case Control Consortium

    A list of members and affiliations appears in the Supplementary Note.

Authors

  1. Search for Panos Deloukas in:

  2. Search for Stavroula Kanoni in:

  3. Search for Christina Willenborg in:

  4. Search for Martin Farrall in:

  5. Search for Themistocles L Assimes in:

  6. Search for John R Thompson in:

  7. Search for Erik Ingelsson in:

  8. Search for Danish Saleheen in:

  9. Search for Jeanette Erdmann in:

  10. Search for Benjamin A Goldstein in:

  11. Search for Kathleen Stirrups in:

  12. Search for Inke R König in:

  13. Search for Jean-Baptiste Cazier in:

  14. Search for Åsa Johansson in:

  15. Search for Alistair S Hall in:

  16. Search for Jong-Young Lee in:

  17. Search for Cristen J Willer in:

  18. Search for John C Chambers in:

  19. Search for Tõnu Esko in:

  20. Search for Lasse Folkersen in:

  21. Search for Anuj Goel in:

  22. Search for Elin Grundberg in:

  23. Search for Aki S Havulinna in:

  24. Search for Weang K Ho in:

  25. Search for Jemma C Hopewell in:

  26. Search for Niclas Eriksson in:

  27. Search for Marcus E Kleber in:

  28. Search for Kati Kristiansson in:

  29. Search for Per Lundmark in:

  30. Search for Leo-Pekka Lyytikäinen in:

  31. Search for Suzanne Rafelt in:

  32. Search for Dmitry Shungin in:

  33. Search for Rona J Strawbridge in:

  34. Search for Gudmar Thorleifsson in:

  35. Search for Emmi Tikkanen in:

  36. Search for Natalie Van Zuydam in:

  37. Search for Benjamin F Voight in:

  38. Search for Lindsay L Waite in:

  39. Search for Weihua Zhang in:

  40. Search for Andreas Ziegler in:

  41. Search for Devin Absher in:

  42. Search for David Altshuler in:

  43. Search for Anthony J Balmforth in:

  44. Search for Inês Barroso in:

  45. Search for Peter S Braund in:

  46. Search for Christof Burgdorf in:

  47. Search for Simone Claudi-Boehm in:

  48. Search for David Cox in:

  49. Search for Maria Dimitriou in:

  50. Search for Ron Do in:

  51. Search for Alex S F Doney in:

  52. Search for NourEddine El Mokhtari in:

  53. Search for Per Eriksson in:

  54. Search for Krista Fischer in:

  55. Search for Pierre Fontanillas in:

  56. Search for Anders Franco-Cereceda in:

  57. Search for Bruna Gigante in:

  58. Search for Leif Groop in:

  59. Search for Stefan Gustafsson in:

  60. Search for Jörg Hager in:

  61. Search for Göran Hallmans in:

  62. Search for Bok-Ghee Han in:

  63. Search for Sarah E Hunt in:

  64. Search for Hyun M Kang in:

  65. Search for Thomas Illig in:

  66. Search for Thorsten Kessler in:

  67. Search for Joshua W Knowles in:

  68. Search for Genovefa Kolovou in:

  69. Search for Johanna Kuusisto in:

  70. Search for Claudia Langenberg in:

  71. Search for Cordelia Langford in:

  72. Search for Karin Leander in:

  73. Search for Marja-Liisa Lokki in:

  74. Search for Anders Lundmark in:

  75. Search for Mark I McCarthy in:

  76. Search for Christa Meisinger in:

  77. Search for Olle Melander in:

  78. Search for Evelin Mihailov in:

  79. Search for Seraya Maouche in:

  80. Search for Andrew D Morris in:

  81. Search for Martina Müller-Nurasyid in:

  82. Search for Kjell Nikus in:

  83. Search for John F Peden in:

  84. Search for N William Rayner in:

  85. Search for Asif Rasheed in:

  86. Search for Silke Rosinger in:

  87. Search for Diana Rubin in:

  88. Search for Moritz P Rumpf in:

  89. Search for Arne Schäfer in:

  90. Search for Mohan Sivananthan in:

  91. Search for Ci Song in:

  92. Search for Alexandre F R Stewart in:

  93. Search for Sian-Tsung Tan in:

  94. Search for Gudmundur Thorgeirsson in:

  95. Search for C Ellen van der Schoot in:

  96. Search for Peter J Wagner in:

  97. Search for George A Wells in:

  98. Search for Philipp S Wild in:

  99. Search for Tsun-Po Yang in:

  100. Search for Philippe Amouyel in:

  101. Search for Dominique Arveiler in:

  102. Search for Hanneke Basart in:

  103. Search for Michael Boehnke in:

  104. Search for Eric Boerwinkle in:

  105. Search for Paolo Brambilla in:

  106. Search for Francois Cambien in:

  107. Search for Adrienne L Cupples in:

  108. Search for Ulf de Faire in:

  109. Search for Abbas Dehghan in:

  110. Search for Patrick Diemert in:

  111. Search for Stephen E Epstein in:

  112. Search for Alun Evans in:

  113. Search for Marco M Ferrario in:

  114. Search for Jean Ferrières in:

  115. Search for Dominique Gauguier in:

  116. Search for Alan S Go in:

  117. Search for Alison H Goodall in:

  118. Search for Villi Gudnason in:

  119. Search for Stanley L Hazen in:

  120. Search for Hilma Holm in:

  121. Search for Carlos Iribarren in:

  122. Search for Yangsoo Jang in:

  123. Search for Mika Kähönen in:

  124. Search for Frank Kee in:

  125. Search for Hyo-Soo Kim in:

  126. Search for Norman Klopp in:

  127. Search for Wolfgang Koenig in:

  128. Search for Wolfgang Kratzer in:

  129. Search for Kari Kuulasmaa in:

  130. Search for Markku Laakso in:

  131. Search for Reijo Laaksonen in:

  132. Search for Ji-Young Lee in:

  133. Search for Lars Lind in:

  134. Search for Willem H Ouwehand in:

  135. Search for Sarah Parish in:

  136. Search for Jeong E Park in:

  137. Search for Nancy L Pedersen in:

  138. Search for Annette Peters in:

  139. Search for Thomas Quertermous in:

  140. Search for Daniel J Rader in:

  141. Search for Veikko Salomaa in:

  142. Search for Eric Schadt in:

  143. Search for Svati H Shah in:

  144. Search for Juha Sinisalo in:

  145. Search for Klaus Stark in:

  146. Search for Kari Stefansson in:

  147. Search for David-Alexandre Trégouët in:

  148. Search for Jarmo Virtamo in:

  149. Search for Lars Wallentin in:

  150. Search for Nicholas Wareham in:

  151. Search for Martina E Zimmermann in:

  152. Search for Markku S Nieminen in:

  153. Search for Christian Hengstenberg in:

  154. Search for Manjinder S Sandhu in:

  155. Search for Tomi Pastinen in:

  156. Search for Ann-Christine Syvänen in:

  157. Search for G Kees Hovingh in:

  158. Search for George Dedoussis in:

  159. Search for Paul W Franks in:

  160. Search for Terho Lehtimäki in:

  161. Search for Andres Metspalu in:

  162. Search for Pierre A Zalloua in:

  163. Search for Agneta Siegbahn in:

  164. Search for Stefan Schreiber in:

  165. Search for Samuli Ripatti in:

  166. Search for Stefan S Blankenberg in:

  167. Search for Markus Perola in:

  168. Search for Robert Clarke in:

  169. Search for Bernhard O Boehm in:

  170. Search for Christopher O'Donnell in:

  171. Search for Muredach P Reilly in:

  172. Search for Winfried März in:

  173. Search for Rory Collins in:

  174. Search for Sekar Kathiresan in:

  175. Search for Anders Hamsten in:

  176. Search for Jaspal S Kooner in:

  177. Search for Unnur Thorsteinsdottir in:

  178. Search for John Danesh in:

  179. Search for Colin N A Palmer in:

  180. Search for Robert Roberts in:

  181. Search for Hugh Watkins in:

  182. Search for Heribert Schunkert in:

  183. Search for Nilesh J Samani in:

Contributions

Writing committee: P. Deloukas, S. Kanoni, C.W., M.F., T.L.A., J.R.T., E.I., D. Saleheen, J.E., M.P. Reilly, R. Collins, S. Kathiresan, A.H., U.T., J.S.K., J.D., C.N.A.P., R.R., H.W., H.S. and N.J.S. Steering committee: P. Deloukas, S. Kanoni, C.W., M.F., T.L.A., J.R.T., E.I., D. Saleheen, J.E., M.P. Reilly, R. Collins, S. Kathiresan, A.H., U.T., J.S.K., J.D., C.N.A.P., R.R., H.W., H.S., N.J.S., S.S.B., B.O.B., J.C.C., R. Clarke, G.D., P.W.F., C.H., G.K.H., Jong-Young Lee, T.L., W.M., A.M., M.S.N., C.O., M.P., S. Ripatti, M.S.S., S.S., A. Siegbahn, C.J.W. and P.A.Z. Analysis committee: B.A.G., K. Stirrups, I.R.K., J.-B.C., Å.J., T.E., L.F., A.G., A.S. Havulinna, W.K.H., J.C.H., N.E., M.E.K., K. Kristiansson, P.L., L.-P.L., S. Rafelt, D. Shungin, R.J.S., G. Thorleifsson, E.T., N.V.Z., B.F.V., L.L.W., W.Z. and A.Z. Genotyping: D. Absher, I.B., C.B., S.C.-B., DIAGRAM Consortium, N.E.M., K.F., P.F., B.G., L.G., S.G., J.H., B.-G.H., S.E.H., T.K., J.W.K., C. Langenberg, C. Langford, M.I.M., M.M.-N., K.N., J.F.P., S. Rosinger, D.R., M.P. Rumpf, A. Schäfer, A.F.R.S., P.J.W. and Wellcome Trust Case Control Consortium. Array design: H.M.K. and N.W.R. Functional analyses: E.G., P.E., A.F.-C., A.L., O.M., S.M., MuTHER Consortium, T.-P.Y., A.H.G., E.S., T.P. and A.-C.S. Samples and phenotyping: (ADVANCE) A.S.G., C.I. and T.Q.; (AMC-PAS/SANQUIN) C.E.v.d.S. and H.B.; (Angio-Lüb/KORA) P. Diemert; (CADomics) P.S.W.; (CARDIOGENICS) F.C. and W.H.O.; (CHARGE) E.B., A.L.C., A.D. and V.G.; (Corogene) M.-L.L. and J.S.; (deCODE) G. Thorgeirsson, H.H. and K. Stefansson; (EPIC-NORFOLK) N.W.; (Estonian Biobank) E.M.; (FGENTCARD) D.G.; (FINCAVAS) M.K.; (FINRISK 2007/DILGOM) V.S.; (FRISCII) L.W.; (GerMIFS) T.I., C.M., K. Stark and M.E.Z.; (GLACIER) G.H.; (GoDARTS Dundee) A.S.F.D. and A.D.M.; (HPS) S.P.; (Korean GenRIC) Y.J., H.-S.K., Ji-Young Lee and J.E.P.; (LOLIPOP) S.-T.T.; (LURIC/AtheroRemo) R.L. and W. Koenig; (METSIM) J.K., M.B. and M.L.; (MIGen) R.D.; (MORGAM) K. Kuulasmaa, J.V., P.A., D. Arveiler., J.F., D.-A.T., N.K., A.P., P.B., M.M.F., A.E. and F.K.; (Ottawa Heart Genomics Study) G.A.W., S.L.H. and S.H.S.; (PennCATH/MedStar) S.E.E. and D.J.R.; (Pfizer-Broad-Malmo) D. Altshuler and D.C.; (PIVUS/Swedish Twin Registry) C.S., L.L. and N.L.P.; (PROMIS) A.R.; (SHEEP-SCARF) K.L. and U.d.F.; (THISEAS) M.D., G.K.; (Ulm-EMIL) W. Kratzer; and (WTCCC) A.J.B., P.S.B., M.S. and A.S. Hall.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Panos Deloukas or Nilesh J Samani.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–7, Supplementary Tables 1–8 and Supplementary Note

Excel files

  1. 1.

    Supplementary Table 9

    SNPs at an FDR5% and LD threshold of r2 < 0.2 used in estimating heritability

  2. 2.

    Supplementary Table 10

    Network molecules

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.2480

Further reading