Large-scale association analysis identifies new risk loci for coronary artery disease (original) (raw)

References

1. Berry, J.D. et al. Lifetime risks of cardiovascular disease. N. Engl. J. Med. 366, 321–329 (2012).
   Article CAS PubMed PubMed Central Google Scholar
2. Peden, J.F. & Farrall, M. Thirty-five common variants for coronary artery disease: the fruits of much collaborative labour. Hum. Mol. Genet. 20 R2, R198–R205 (2011).
   Article CAS PubMed PubMed Central Google Scholar
3. Kingsmore, S.F., Lindquist, I.E., Mudge, J., Gessler, D.D. & Beavis, W.D. Genome-wide association studies: progress and potential for drug discovery and development. Nat. Rev. Drug Discov. 7, 221–230 (2008).
   Article CAS PubMed PubMed Central Google Scholar
4. Stein, E.A. et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N. Engl. J. Med. 366, 1108–1118 (2012).
   Article CAS PubMed Google Scholar
5. Schunkert, H. et al. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat. Genet. 43, 333–338 (2011).
   Article CAS PubMed PubMed Central Google Scholar
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. Clarke, R. et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N. Engl. J. Med. 361, 2518–2528 (2009).
   Article CAS PubMed Google Scholar
8. Samani, N.J. et al. Genomewide association analysis of coronary artery disease. N. Engl. J. Med. 357, 443–453 (2007).
   Article CAS PubMed PubMed Central Google Scholar
9. Erdmann, J. et al. New susceptibility locus for coronary artery disease on chromosome 3q22.3. Nat. Genet. 41, 280–282 (2009).
   Article CAS PubMed PubMed Central Google Scholar
10. Kathiresan, S. et al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat. Genet. 41, 334–341 (2009).
    Article CAS PubMed Google Scholar
11. Soranzo, N. 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).
    Article CAS PubMed PubMed Central Google Scholar
12. Wang, F. et al. Genome-wide association identifies a susceptibility locus for coronary artery disease in the Chinese Han population. Nat. Genet. 43, 345–349 (2011).
    Article CAS PubMed Google Scholar
13. The IBC 50K CAD Consortium. Large-scale gene-centric analysis identifies novel variants for coronary artery disease. PLoS Genet. 7, e1002260 (2011).
14. Yang, J. et al. Genome partitioning of genetic variation for complex traits using common SNPs. Nat. Genet. 43, 519–525 (2011).
    Article CAS PubMed PubMed Central Google Scholar
15. Voight, B.F. et al. The Metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits. PLoS Genet. 8, e1002793 (2012).
    CAS PubMed PubMed Central Google Scholar
16. Teslovich, T.M. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–713 (2010).
    Article CAS PubMed PubMed Central Google Scholar
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. Voight, B.F. et al. Twelve type 2 diabetes susceptibility loci identified through large scale association analysis. Nat. Genet. 42, 579–589 (2010).
    Article CAS PubMed PubMed Central Google Scholar
19. Dupuis, J. et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat. Genet. 42, 105–116 (2010).
    Article CAS PubMed PubMed Central Google Scholar
20. Speliotes, E.K. et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat. Genet. 42, 937–948 (2010).
    Article CAS PubMed PubMed Central Google Scholar
21. Yang, J. et al. Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits. Nat. Genet. 44, 369–375 (2012).
    Article CAS PubMed PubMed Central Google Scholar
22. Ken-Dror, G., Talmud, P.J., Humphries, S.E. & Dreno, F. 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).
    Article CAS PubMed PubMed Central Google Scholar
23. Reilly, M.P. 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).
    Article CAS PubMed PubMed Central Google Scholar
24. Heid, I.M. 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).
    Article CAS PubMed PubMed Central Google Scholar
25. Storey, J.D. & Tibshirani, R. Statistical methods for identifying differentially expressed genes in DNA microarrays. Methods Mol. Biol. 224, 149–157 (2003).
    CAS PubMed Google Scholar
26. Hansson, G.K., Libby, P., Schönbeck, U. & Yan, Z.-Q. Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ. Res. 91, 281–291 (2002).
    Article CAS PubMed Google Scholar
27. Emerging Risk Factors Collaboration. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N. Engl. J. Med. 364, 829–841 (2011).
28. Mozaffarian, D. 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).
    Article CAS PubMed Google Scholar
29. Turnbull, F.M. et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 52, 2288–2298 (2009).
    Article CAS PubMed Google Scholar
30. Ross, R. Atherosclerosis is an inflammatory disease. Am. Heart J. 138, S419–S420 (1999).
    Article CAS PubMed Google Scholar
31. Folkersen, L. 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).
    Article CAS PubMed Google Scholar
32. Grundberg, E. et al. Mapping _cis_- and _trans_-regulatory effects across multiple tissues in twins: the MuTHER Study. Nat. Genet. 44, 1084–1089 (2012).
    Article CAS PubMed PubMed Central Google Scholar
33. Schadt, E.E. et al. Mapping the genetic architecture of gene expression in human liver. PLoS Biol. 6, e107 (2008).
    Article PubMed PubMed Central Google Scholar
34. Ge, B. et al. Global patterns of cis variation in human cells revealed by high-density allelic expression analysis. Nat. Genet. 41, 1216–1222 (2009).
    Article CAS PubMed Google Scholar

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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

1. 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 and Nilesh J Samani: These authors contributed equally to this work.

Authors and 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. Radcliffe Department of Medicine, Cardiovascular 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. Department of Medicine, Atherosclerosis Research Unit, 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. Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit, 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. Department of Molecular Medicine and Surgery, Cardiothoracic Surgery Unit, 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. Department of Cardiology, Heart Centre, 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. Department of Clinical and Experimental Medicine, Research Centre for Epidemiology and Preventive Medicine (EPIMED), 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,
     Wolfgang Kratzer & Reijo Laaksonen
108. Tampere, Finland
     Wolfgang Kratzer & Reijo Laaksonen
109. Department of Haematology, University of Cambridge, Cambridge, UK
     Willem H Ouwehand
110. National Health Service (NHS) Blood and Transplant, Cambridge, UK
     Willem H Ouwehand
111. Division of Cardiology, Samsung Medical Center, Seoul, Korea
     Jeong E Park
112. Munich Heart Alliance, Munich, Germany
     Annette Peters
113. 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
114. Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, USA
     Eric Schadt
115. Department of Medicine, Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, USA
     Svati H Shah
116. Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
     Svati H Shah
117. Division of Cardiology, Department of Medicine, Helsinki University Central Hospital (HUCH), Helsinki, Finland
     Juha Sinisalo & Markku S Nieminen
118. Klinik und Poliklinik für Innere Medizin II, Regensburg, Germany
     Klaus Stark, Martina E Zimmermann & Christian Hengstenberg
119. Department of Human Genetics, McGill University, Montréal, Québec, Canada
     Tomi Pastinen
120. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA
     Paul W Franks
121. Lebanese American University, Chouran, Beirut, Lebanon
     Pierre A Zalloua
122. Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
     Muredach P Reilly
123. Synlab Academy, Mannheim, Germany
     Winfried März
124. Cardiology Division, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
     Sekar Kathiresan
125. Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
     Sekar Kathiresan

Authors

1. Panos Deloukas
2. Stavroula Kanoni
3. Christina Willenborg
4. Martin Farrall
5. Themistocles L Assimes
6. John R Thompson
7. Erik Ingelsson
8. Danish Saleheen
9. Jeanette Erdmann
10. Benjamin A Goldstein
11. Kathleen Stirrups
12. Inke R König
13. Jean-Baptiste Cazier
14. Åsa Johansson
15. Alistair S Hall
16. Jong-Young Lee
17. Cristen J Willer
18. John C Chambers
19. Tõnu Esko
20. Lasse Folkersen
21. Anuj Goel
22. Elin Grundberg
23. Aki S Havulinna
24. Weang K Ho
25. Jemma C Hopewell
26. Niclas Eriksson
27. Marcus E Kleber
28. Kati Kristiansson
29. Per Lundmark
30. Leo-Pekka Lyytikäinen
31. Suzanne Rafelt
32. Dmitry Shungin
33. Rona J Strawbridge
34. Gudmar Thorleifsson
35. Emmi Tikkanen
36. Natalie Van Zuydam
37. Benjamin F Voight
38. Lindsay L Waite
39. Weihua Zhang
40. Andreas Ziegler
41. Devin Absher
42. David Altshuler
43. Anthony J Balmforth
44. Inês Barroso
45. Peter S Braund
46. Christof Burgdorf
47. Simone Claudi-Boehm
48. David Cox
49. Maria Dimitriou
50. Ron Do
51. Alex S F Doney
52. NourEddine El Mokhtari
53. Per Eriksson
54. Krista Fischer
55. Pierre Fontanillas
56. Anders Franco-Cereceda
57. Bruna Gigante
58. Leif Groop
59. Stefan Gustafsson
60. Jörg Hager
61. Göran Hallmans
62. Bok-Ghee Han
63. Sarah E Hunt
64. Hyun M Kang
65. Thomas Illig
66. Thorsten Kessler
67. Joshua W Knowles
68. Genovefa Kolovou
69. Johanna Kuusisto
70. Claudia Langenberg
71. Cordelia Langford
72. Karin Leander
73. Marja-Liisa Lokki
74. Anders Lundmark
75. Mark I McCarthy
76. Christa Meisinger
77. Olle Melander
78. Evelin Mihailov
79. Seraya Maouche
80. Andrew D Morris
81. Martina Müller-Nurasyid
82. Kjell Nikus
83. John F Peden
84. N William Rayner
85. Asif Rasheed
86. Silke Rosinger
87. Diana Rubin
88. Moritz P Rumpf
89. Arne Schäfer
90. Mohan Sivananthan
91. Ci Song
92. Alexandre F R Stewart
93. Sian-Tsung Tan
94. C Ellen van der Schoot
95. Peter J Wagner
96. George A Wells
97. Philipp S Wild
98. Tsun-Po Yang
99. Philippe Amouyel
100. Dominique Arveiler
101. Hanneke Basart
102. Michael Boehnke
103. Eric Boerwinkle
104. Paolo Brambilla
105. Francois Cambien
106. Adrienne L Cupples
107. Ulf de Faire
108. Abbas Dehghan
109. Patrick Diemert
110. Stephen E Epstein
111. Alun Evans
112. Marco M Ferrario
113. Jean Ferrières
114. Dominique Gauguier
115. Alan S Go
116. Alison H Goodall
117. Villi Gudnason
118. Stanley L Hazen
119. Hilma Holm
120. Carlos Iribarren
121. Yangsoo Jang
122. Mika Kähönen
123. Frank Kee
124. Hyo-Soo Kim
125. Norman Klopp
126. Wolfgang Koenig
127. Wolfgang Kratzer
128. Kari Kuulasmaa
129. Markku Laakso
130. Reijo Laaksonen
131. Ji-Young Lee
132. Lars Lind
133. Willem H Ouwehand
134. Sarah Parish
135. Jeong E Park
136. Nancy L Pedersen
137. Annette Peters
138. Thomas Quertermous
139. Daniel J Rader
140. Veikko Salomaa
141. Eric Schadt
142. Svati H Shah
143. Juha Sinisalo
144. Klaus Stark
145. Kari Stefansson
146. David-Alexandre Trégouët
147. Jarmo Virtamo
148. Lars Wallentin
149. Nicholas Wareham
150. Martina E Zimmermann
151. Markku S Nieminen
152. Christian Hengstenberg
153. Manjinder S Sandhu
154. Tomi Pastinen
155. Ann-Christine Syvänen
156. G Kees Hovingh
157. George Dedoussis
158. Paul W Franks
159. Terho Lehtimäki
160. Andres Metspalu
161. Pierre A Zalloua
162. Agneta Siegbahn
163. Stefan Schreiber
164. Samuli Ripatti
165. Stefan S Blankenberg
166. Markus Perola
167. Robert Clarke
168. Bernhard O Boehm
169. Christopher O'Donnell
170. Muredach P Reilly
171. Winfried März
172. Rory Collins
173. Sekar Kathiresan
174. Anders Hamsten
175. Jaspal S Kooner
176. Unnur Thorsteinsdottir
177. John Danesh
178. Colin N A Palmer
179. Robert Roberts
180. Hugh Watkins
181. Heribert Schunkert
182. Nilesh J Samani

Consortia

The CARDIoGRAMplusC4D Consortium

DIAGRAM Consortium

CARDIOGENICS Consortium

MuTHER Consortium

Wellcome Trust Case Control Consortium

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.

Corresponding authors

Correspondence toPanos Deloukas or Nilesh J Samani.

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Competing interests

The authors declare no competing financial interests.

Additional information

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

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

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

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

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The CARDIoGRAMplusC4D Consortium., Deloukas, P., Kanoni, S. et al. Large-scale association analysis identifies new risk loci for coronary artery disease.Nat Genet 45, 25–33 (2013). https://doi.org/10.1038/ng.2480

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• Received: 24 April 2012
• Accepted: 02 November 2012
• Published: 02 December 2012
• Issue date: January 2013
• DOI: https://doi.org/10.1038/ng.2480