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

Panos Deloukas; Stavroula Kanoni; Christina Willenborg; Martin Farrall; Themistocles L. Assimes; John R. Thompson; Erik Ingelsson; Danish Saleheen; Jeanette Erdmann; Benjamin A. Goldstein; Kathleen Stirrups; Inke R. König; Jean Baptiste Cazier; Åsa Johansson; Alistair S. Hall; Jong Young Lee; Cristen J. Willer; John C. Chambers; Tõnu Esko; Lasse Folkersen; Anuj Goel; Elin Grundberg; Aki S. Havulinna; Weang K. Ho; Jemma C. Hopewell; Niclas Eriksson; Marcus E. Kleber; Kati Kristiansson; Per Lundmark; Leo Pekka Lyytikäinen; Suzanne Rafelt; Dmitry Shungin; Rona J. Strawbridge; Gudmar Thorleifsson; Emmi Tikkanen; Natalie Van Zuydam; Benjamin F. Voight; Lindsay L. Waite; Weihua Zhang; Andreas Ziegler; Devin Absher; David Altshuler; Anthony J. Balmforth; Inês Barroso; Peter S. Braund; Christof Burgdorf; Simone Claudi-Boehm; David Cox; Maria Dimitriou; Ron Do; Alex S.F. Doney; Nour Eddine El Mokhtari; Per Eriksson; Krista Fischer; Pierre Fontanillas; Anders Franco-Cereceda; Bruna Gigante; Leif Groop; Stefan Gustafsson; Jörg Hager; Göran Hallmans; Bok Ghee Han; Sarah E. Hunt; Hyun M. Kang; Thomas Illig; Thorsten Kessler; Joshua W. Knowles; Genovefa Kolovou; Johanna Kuusisto; Claudia Langenberg; Cordelia Langford; Karin Leander; Marja Liisa Lokki; Anders Lundmark; Mark I. McCarthy; Christa Meisinger; Olle Melander; Evelin Mihailov; Seraya Maouche; Andrew D. Morris; Martina Müller-Nurasyid; Kjell Nikus; John F. Peden; N. William Rayner; Asif Rasheed; Silke Rosinger; Diana Rubin; Moritz P. Rumpf; Arne Schäfer; Mohan Sivananthan; Ci Song; Alexandre F.R. Stewart; Sian Tsung Tan; Gudmundur Thorgeirsson; C. Ellen Van Der Schoot; Peter J. Wagner; George A. Wells; Philipp S. Wild; Tsun Po Yang; Philippe Amouyel; Dominique Arveiler; Hanneke Basart; Michael Boehnke; Eric Boerwinkle; Paolo Brambilla; Francois Cambien; Adrienne L. Cupples; Ulf De Faire; Abbas Dehghan; Patrick Diemert; Stephen E. Epstein; Alun Evans; Marco M. Ferrario; Jean Ferrières; Dominique Gauguier; Alan S. Go; Alison H. Goodall; Villi Gudnason; Stanley L. Hazen; Hilma Holm; Carlos Iribarren; Yangsoo Jang; Mika Kähönen; Frank Kee; Hyo Soo Kim; Norman Klopp; Wolfgang Koenig; Wolfgang Kratzer; Kari Kuulasmaa; Markku Laakso; Reijo Laaksonen; Ji Young Lee; Lars Lind; Willem H. Ouwehand; Sarah Parish; Jeong E. Park; Nancy L. Pedersen; Annette Peters; Thomas Quertermous; Daniel J. Rader; Veikko Salomaa; Eric Schadt; Svati H. Shah; Juha Sinisalo; Klaus Stark; Kari Stefansson; David Alexandre Trégouët; Jarmo Virtamo; Lars Wallentin; Nicholas Wareham; Martina E. Zimmermann; Markku S. Nieminen; Christian Hengstenberg; Manjinder S. Sandhu; Tomi Pastinen; Ann Christine Syvänen; G. Kees Hovingh; George Dedoussis; Paul W. Franks; Terho Lehtimäki; Andres Metspalu; Pierre A. Zalloua; Agneta Siegbahn; Stefan Schreiber; Samuli Ripatti; Stefan S. Blankenberg; Markus Perola; Robert Clarke; Bernhard O. Boehm; Christopher O'Donnell; Muredach P. Reilly; Winfried März; 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

doi:10.1038/ng.2480

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

Panos Deloukas^*, Stavroula Kanoni, Christina Willenborg, Martin Farrall, Themistocles L. Assimes, John R. Thompson, Erik Ingelsson, Danish Saleheen, Jeanette Erdmann, Benjamin A. Goldstein, Kathleen Stirrups, Inke R. König, Jean Baptiste Cazier, Åsa Johansson, Alistair S. Hall, Jong Young Lee, Cristen J. Willer, John C. Chambers, Tõnu Esko, Lasse FolkersenAnuj Goel, Elin Grundberg, Aki S. Havulinna, Weang K. Ho, Jemma C. Hopewell, Niclas Eriksson, Marcus E. Kleber, Kati Kristiansson, Per Lundmark, Leo Pekka Lyytikäinen, Suzanne Rafelt, Dmitry Shungin, Rona J. Strawbridge, Gudmar Thorleifsson, Emmi Tikkanen, Natalie Van Zuydam, Benjamin F. Voight, Lindsay L. Waite, Weihua Zhang, Andreas Ziegler, Devin Absher, David Altshuler, Anthony J. Balmforth, Inês Barroso, Peter S. Braund, Christof Burgdorf, Simone Claudi-Boehm, David Cox, Maria Dimitriou, Ron Do, Alex S.F. Doney, Nour Eddine El Mokhtari, Per Eriksson, Krista Fischer, Pierre Fontanillas, Anders Franco-Cereceda, Bruna Gigante, Leif Groop, Stefan Gustafsson, Jörg Hager, Göran Hallmans, Bok Ghee Han, Sarah E. Hunt, Hyun M. Kang, Thomas Illig, Thorsten Kessler, Joshua W. Knowles, Genovefa Kolovou, Johanna Kuusisto, Claudia Langenberg, Cordelia Langford, Karin Leander, Marja Liisa Lokki, Anders Lundmark, Mark I. McCarthy, Christa Meisinger, Olle Melander, Evelin Mihailov, Seraya Maouche, Andrew D. Morris, Martina Müller-Nurasyid, Kjell Nikus, John F. Peden, N. William Rayner, Asif Rasheed, Silke Rosinger, Diana Rubin, Moritz P. Rumpf, Arne Schäfer, Mohan Sivananthan, Ci Song, Alexandre F.R. Stewart, Sian Tsung Tan, Gudmundur Thorgeirsson, C. Ellen Van Der Schoot, Peter J. Wagner, George A. Wells, Philipp S. Wild, Tsun Po Yang, Philippe Amouyel, Dominique Arveiler, Hanneke Basart, Michael Boehnke, Eric Boerwinkle, Paolo Brambilla, Francois Cambien, Adrienne L. Cupples, Ulf De Faire, Abbas Dehghan, Patrick Diemert, Stephen E. Epstein, Alun Evans, Marco M. Ferrario, Jean Ferrières, Dominique Gauguier, Alan S. Go, Alison H. Goodall, Villi Gudnason, Stanley L. Hazen, Hilma Holm, Carlos Iribarren, Yangsoo Jang, Mika Kähönen, Frank Kee, Hyo Soo Kim, Norman Klopp, Wolfgang Koenig, Wolfgang Kratzer, Kari Kuulasmaa, Markku Laakso, Reijo Laaksonen, Ji Young Lee, Lars Lind, Willem H. Ouwehand, Sarah Parish, Jeong E. Park, Nancy L. Pedersen, Annette Peters, Thomas Quertermous, Daniel J. Rader, Veikko Salomaa, Eric Schadt, Svati H. Shah, Juha Sinisalo, Klaus Stark, Kari Stefansson, David Alexandre Trégouët, Jarmo Virtamo, Lars Wallentin, Nicholas Wareham, Martina E. Zimmermann, Markku S. Nieminen, Christian Hengstenberg, Manjinder S. Sandhu, Tomi Pastinen, Ann Christine Syvänen, G. Kees Hovingh, George Dedoussis, Paul W. Franks, Terho Lehtimäki, Andres Metspalu, Pierre A. Zalloua, Agneta Siegbahn, Stefan Schreiber, Samuli Ripatti, Stefan S. Blankenberg, Markus Perola, Robert Clarke, Bernhard O. Boehm, Christopher O'Donnell, Muredach P. Reilly, Winfried März, 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

^*Corresponding author for this work

1399 Citations (Scopus)

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 (r 2 < 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.

Original language	English
Journal	Nature Genetics
Volume	45
Issue number	1
Pages (from-to)	25-33
Number of pages	9
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.2480
Publication status	Published - 01.01.2013

Funding

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 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. 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. 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. 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. 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. 1Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. 2Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany. 3Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. 4Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. 5Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. 6Department of Health Sciences, University of Leicester, Leicester, UK. 7Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 8Center for Non-Communicable Diseases, Karachi, Pakistan. 9Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. 10Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 11Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany. 12Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden. 13Division of Cardiovascular and Neuronal Remodelling, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK. 14Center for Genome Science, Korea National Institute of Health, Korea Center for Disease Control and Prevention, Yeonje-ri, Chungwon-gun, Korea. 15Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. 16Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA. 17Department of Epidemiology and Biostatistics, Imperial College London, London, UK. 18Estonian Genome Center, University of Tartu, Tartu, Estonia. 19Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. 20Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. 21Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden. 22Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK. 23Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland. 24Clinical Trial Service Unit, University of Oxford, Oxford, UK. 25Epidemiological Studies Unit, University of Oxford, Oxford, UK. 26Mannheim Institute of Public Health, Social and Preventive Medicine, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany. 27Ludwigshafen Risk and Cardiovascular Health (LURIC) Study, Freiburg, Germany. 28Department of Medical Sciences, Uppsala University, Uppsala, Sweden. 29Department of Clinical Chemistry, Fimlab Laboratories, Tampere University Hospital, Tampere, Finland. 30Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland. 31Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK. 32Genetic & Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University Diabetes Center, Skåne University Hospital, Malmö, Sweden. 33Department of Public Health & Clinical Medicine, Genetic Epidemiology & Clinical Research Group, Section for Medicine, Umeå University, Umeå, Sweden. 34Department of Odontology, Umeå University, Umeå, Sweden. 35deCODE Genetics, Reykjavik, Iceland. 36Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland. 37Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland. 38Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK. 39Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 40HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA. 41Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. 42Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA. 43Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. 44Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. 45Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK. 46University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK. 47National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK. 48Deutsches Herzzentrum München, Technische Universität München, Munich, Germany. 49Practice of Gynecology, Ulm University Medical Centre, Ulm, Germany. 50Biotherapeutics and Bioinnovation Center, Pfizer, South San Francisco, California, USA. 51Department of Dietetics–Nutrition, Harokopio University, Athens, Greece. 52A list of members and affiliations appears in the supplementary Note. 53Klinik für Innere Medizin, Kreiskrankenhaus Rendsburg, Rendsburg, Germany. 54Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. 55Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. 56Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmö, Malmö, Sweden. 57Commissariat à l′Energie Atomique (CEA)–Genomics Institute, National Genotyping Centre, Paris, France. 58Department of Public Health & Clinical Medicine, Section for Nutritional Research, Umeå University, Umeå, Sweden. 59Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA. 60Hannover Unified Biobank, Hannover Medical School, Hannover, Germany. 61First Cardiology Department, Onassis Cardiac Surgery Center 356, Athens, Greece. 62Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland. 63Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK. 64Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland. 65Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK. 66Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK.

Research Areas and Centers

Research Area: Medical Genetics

DFG Research Classification Scheme

2.22-12 Cardiology, Angiology
2.11-05 General Genetics and Functional Genome Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/ng.2480

Cite this

Deloukas, P., Kanoni, S., Willenborg, C., Farrall, M., Assimes, T. L., Thompson, J. R., Ingelsson, E., Saleheen, D., Erdmann, J., Goldstein, B. A., Stirrups, K., König, I. R., Cazier, J. B., Johansson, Å., Hall, A. S., Lee, J. Y., Willer, C. J., Chambers, J. C., Esko, T., ... Samani, N. J. (2013). Large-scale association analysis identifies new risk loci for coronary artery disease. Nature Genetics, 45(1), 25-33. https://doi.org/10.1038/ng.2480

@article{1f27f59f88f84e10a5b165746bb8183d,

title = "Large-scale association analysis identifies new risk loci for coronary artery disease",

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 (r 2 < 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.",

author = "Panos Deloukas and Stavroula Kanoni and Christina Willenborg and Martin Farrall and Assimes, \{Themistocles L.\} and Thompson, \{John R.\} and Erik Ingelsson and Danish Saleheen and Jeanette Erdmann and Goldstein, \{Benjamin A.\} and Kathleen Stirrups and K{\"o}nig, \{Inke R.\} and Cazier, \{Jean Baptiste\} and {\AA}sa Johansson and Hall, \{Alistair S.\} and Lee, \{Jong Young\} and Willer, \{Cristen J.\} and Chambers, \{John C.\} and T{\~o}nu Esko and Lasse Folkersen and Anuj Goel and Elin Grundberg and Havulinna, \{Aki S.\} and Ho, \{Weang K.\} and Hopewell, \{Jemma C.\} and Niclas Eriksson and Kleber, \{Marcus E.\} and Kati Kristiansson and Per Lundmark and Lyytik{\"a}inen, \{Leo Pekka\} and Suzanne Rafelt and Dmitry Shungin and Strawbridge, \{Rona J.\} and Gudmar Thorleifsson and Emmi Tikkanen and \{Van Zuydam\}, Natalie and Voight, \{Benjamin F.\} and Waite, \{Lindsay L.\} and Weihua Zhang and Andreas Ziegler and Devin Absher and David Altshuler and Balmforth, \{Anthony J.\} and In{\^e}s Barroso and Braund, \{Peter S.\} and Christof Burgdorf and Simone Claudi-Boehm and David Cox and Maria Dimitriou and Ron Do and Doney, \{Alex S.F.\} and \{El Mokhtari\}, \{Nour Eddine\} and Per Eriksson and Krista Fischer and Pierre Fontanillas and Anders Franco-Cereceda and Bruna Gigante and Leif Groop and Stefan Gustafsson and J{\"o}rg Hager and G{\"o}ran Hallmans and Han, \{Bok Ghee\} and Hunt, \{Sarah E.\} and Kang, \{Hyun M.\} and Thomas Illig and Thorsten Kessler and Knowles, \{Joshua W.\} and Genovefa Kolovou and Johanna Kuusisto and Claudia Langenberg and Cordelia Langford and Karin Leander and Lokki, \{Marja Liisa\} and Anders Lundmark and McCarthy, \{Mark I.\} and Christa Meisinger and Olle Melander and Evelin Mihailov and Seraya Maouche and Morris, \{Andrew D.\} and Martina M{\"u}ller-Nurasyid and Kjell Nikus and Peden, \{John F.\} and Rayner, \{N. William\} and Asif Rasheed and Silke Rosinger and Diana Rubin and Rumpf, \{Moritz P.\} and Arne Sch{\"a}fer and Mohan Sivananthan and Ci Song and Stewart, \{Alexandre F.R.\} and Tan, \{Sian Tsung\} and Gudmundur Thorgeirsson and \{Van Der Schoot\}, \{C. Ellen\} and Wagner, \{Peter J.\} and Wells, \{George A.\} and Wild, \{Philipp S.\} and Yang, \{Tsun Po\} and Philippe Amouyel and Dominique Arveiler and Hanneke Basart and Michael Boehnke and Eric Boerwinkle and Paolo Brambilla and Francois Cambien and Cupples, \{Adrienne L.\} and \{De Faire\}, Ulf and Abbas Dehghan and Patrick Diemert and Epstein, \{Stephen E.\} and Alun Evans and Ferrario, \{Marco M.\} and Jean Ferri{\`e}res and Dominique Gauguier and Go, \{Alan S.\} and Goodall, \{Alison H.\} and Villi Gudnason and Hazen, \{Stanley L.\} and Hilma Holm and Carlos Iribarren and Yangsoo Jang and Mika K{\"a}h{\"o}nen and Frank Kee and Kim, \{Hyo Soo\} and Norman Klopp and Wolfgang Koenig and Wolfgang Kratzer and Kari Kuulasmaa and Markku Laakso and Reijo Laaksonen and Lee, \{Ji Young\} and Lars Lind and Ouwehand, \{Willem H.\} and Sarah Parish and Park, \{Jeong E.\} and Pedersen, \{Nancy L.\} and Annette Peters and Thomas Quertermous and Rader, \{Daniel J.\} and Veikko Salomaa and Eric Schadt and Shah, \{Svati H.\} and Juha Sinisalo and Klaus Stark and Kari Stefansson and Tr{\'e}gou{\"e}t, \{David Alexandre\} and Jarmo Virtamo and Lars Wallentin and Nicholas Wareham and Zimmermann, \{Martina E.\} and Nieminen, \{Markku S.\} and Christian Hengstenberg and Sandhu, \{Manjinder S.\} and Tomi Pastinen and Syv{\"a}nen, \{Ann Christine\} and Hovingh, \{G. Kees\} and George Dedoussis and Franks, \{Paul W.\} and Terho Lehtim{\"a}ki and Andres Metspalu and Zalloua, \{Pierre A.\} and Agneta Siegbahn and Stefan Schreiber and Samuli Ripatti and Blankenberg, \{Stefan S.\} and Markus Perola and Robert Clarke and Boehm, \{Bernhard O.\} and Christopher O'Donnell and Reilly, \{Muredach P.\} and Winfried M{\"a}rz and Rory Collins and Sekar Kathiresan and Anders Hamsten and Kooner, \{Jaspal S.\} and Unnur Thorsteinsdottir and John Danesh and Palmer, \{Colin N.A.\} and Robert Roberts and Hugh Watkins and Heribert Schunkert and Samani, \{Nilesh J.\}",

year = "2013",

month = jan,

day = "1",

doi = "10.1038/ng.2480",

language = "English",

volume = "45",

pages = "25--33",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "1",

}

Deloukas, P, Kanoni, S, Willenborg, C, Farrall, M, Assimes, TL, Thompson, JR, Ingelsson, E, Saleheen, D, Erdmann, J, Goldstein, BA, Stirrups, K, König, IR, Cazier, JB, Johansson, Å, Hall, AS, Lee, JY, Willer, CJ, Chambers, JC, Esko, T, Folkersen, L, Goel, A, Grundberg, E, Havulinna, AS, Ho, WK, Hopewell, JC, Eriksson, N, Kleber, ME, Kristiansson, K, Lundmark, P, Lyytikäinen, LP, Rafelt, S, Shungin, D, Strawbridge, RJ, Thorleifsson, G, Tikkanen, E, Van Zuydam, N, Voight, BF, Waite, LL, Zhang, W, Ziegler, A, Absher, D, Altshuler, D, Balmforth, AJ, Barroso, I, Braund, PS, Burgdorf, C, Claudi-Boehm, S, Cox, D, Dimitriou, M, Do, R, Doney, ASF, El Mokhtari, NE, Eriksson, P, Fischer, K, Fontanillas, P, Franco-Cereceda, A, Gigante, B, Groop, L, Gustafsson, S, Hager, J, Hallmans, G, Han, BG, Hunt, SE, Kang, HM, Illig, T, Kessler, T, Knowles, JW, Kolovou, G, Kuusisto, J, Langenberg, C, Langford, C, Leander, K, Lokki, ML, Lundmark, A, McCarthy, MI, Meisinger, C, Melander, O, Mihailov, E, Maouche, S, Morris, AD, Müller-Nurasyid, M, Nikus, K, Peden, JF, Rayner, NW, Rasheed, A, Rosinger, S, Rubin, D, Rumpf, MP, Schäfer, A, Sivananthan, M, Song, C, Stewart, AFR, Tan, ST, Thorgeirsson, G, Van Der Schoot, CE, Wagner, PJ, Wells, GA, Wild, PS, Yang, TP, Amouyel, P, Arveiler, D, Basart, H, Boehnke, M, Boerwinkle, E, Brambilla, P, Cambien, F, Cupples, AL, De Faire, U, Dehghan, A, Diemert, P, Epstein, SE, Evans, A, Ferrario, MM, Ferrières, J, Gauguier, D, Go, AS, Goodall, AH, Gudnason, V, Hazen, SL, Holm, H, Iribarren, C, Jang, Y, Kähönen, M, Kee, F, Kim, HS, Klopp, N, Koenig, W, Kratzer, W, Kuulasmaa, K, Laakso, M, Laaksonen, R, Lee, JY, Lind, L, Ouwehand, WH, Parish, S, Park, JE, Pedersen, NL, Peters, A, Quertermous, T, Rader, DJ, Salomaa, V, Schadt, E, Shah, SH, Sinisalo, J, Stark, K, Stefansson, K, Trégouët, DA, Virtamo, J, Wallentin, L, Wareham, N, Zimmermann, ME, Nieminen, MS, Hengstenberg, C, Sandhu, MS, Pastinen, T, Syvänen, AC, Hovingh, GK, Dedoussis, G, Franks, PW, Lehtimäki, T, Metspalu, A, Zalloua, PA, Siegbahn, A, Schreiber, S, Ripatti, S, Blankenberg, SS, Perola, M, Clarke, R, Boehm, BO, O'Donnell, C, Reilly, MP, März, W, Collins, R, Kathiresan, S, Hamsten, A, Kooner, JS, Thorsteinsdottir, U, Danesh, J, Palmer, CNA, Roberts, R, Watkins, H, Schunkert, H & Samani, NJ 2013, 'Large-scale association analysis identifies new risk loci for coronary artery disease', Nature Genetics, vol. 45, no. 1, pp. 25-33. https://doi.org/10.1038/ng.2480

TY - JOUR

T1 - Large-scale association analysis identifies new risk loci for coronary artery disease

AU - Deloukas, Panos

AU - Kanoni, Stavroula

AU - Willenborg, Christina

AU - Farrall, Martin

AU - Assimes, Themistocles L.

AU - Thompson, John R.

AU - Ingelsson, Erik

AU - Saleheen, Danish

AU - Erdmann, Jeanette

AU - Goldstein, Benjamin A.

AU - Stirrups, Kathleen

AU - König, Inke R.

AU - Cazier, Jean Baptiste

AU - Johansson, Åsa

AU - Hall, Alistair S.

AU - Lee, Jong Young

AU - Willer, Cristen J.

AU - Chambers, John C.

AU - Esko, Tõnu

AU - Folkersen, Lasse

AU - Goel, Anuj

AU - Grundberg, Elin

AU - Havulinna, Aki S.

AU - Ho, Weang K.

AU - Hopewell, Jemma C.

AU - Eriksson, Niclas

AU - Kleber, Marcus E.

AU - Kristiansson, Kati

AU - Lundmark, Per

AU - Lyytikäinen, Leo Pekka

AU - Rafelt, Suzanne

AU - Shungin, Dmitry

AU - Strawbridge, Rona J.

AU - Thorleifsson, Gudmar

AU - Tikkanen, Emmi

AU - Van Zuydam, Natalie

AU - Voight, Benjamin F.

AU - Waite, Lindsay L.

AU - Zhang, Weihua

AU - Ziegler, Andreas

AU - Absher, Devin

AU - Altshuler, David

AU - Balmforth, Anthony J.

AU - Barroso, Inês

AU - Braund, Peter S.

AU - Burgdorf, Christof

AU - Claudi-Boehm, Simone

AU - Cox, David

AU - Dimitriou, Maria

AU - Do, Ron

AU - Doney, Alex S.F.

AU - El Mokhtari, Nour Eddine

AU - Eriksson, Per

AU - Fischer, Krista

AU - Fontanillas, Pierre

AU - Franco-Cereceda, Anders

AU - Gigante, Bruna

AU - Groop, Leif

AU - Gustafsson, Stefan

AU - Hager, Jörg

AU - Hallmans, Göran

AU - Han, Bok Ghee

AU - Hunt, Sarah E.

AU - Kang, Hyun M.

AU - Illig, Thomas

AU - Kessler, Thorsten

AU - Knowles, Joshua W.

AU - Kolovou, Genovefa

AU - Kuusisto, Johanna

AU - Langenberg, Claudia

AU - Langford, Cordelia

AU - Leander, Karin

AU - Lokki, Marja Liisa

AU - Lundmark, Anders

AU - McCarthy, Mark I.

AU - Meisinger, Christa

AU - Melander, Olle

AU - Mihailov, Evelin

AU - Maouche, Seraya

AU - Morris, Andrew D.

AU - Müller-Nurasyid, Martina

AU - Nikus, Kjell

AU - Peden, John F.

AU - Rayner, N. William

AU - Rasheed, Asif

AU - Rosinger, Silke

AU - Rubin, Diana

AU - Rumpf, Moritz P.

AU - Schäfer, Arne

AU - Sivananthan, Mohan

AU - Song, Ci

AU - Stewart, Alexandre F.R.

AU - Tan, Sian Tsung

AU - Thorgeirsson, Gudmundur

AU - Van Der Schoot, C. Ellen

AU - Wagner, Peter J.

AU - Wells, George A.

AU - Wild, Philipp S.

AU - Yang, Tsun Po

AU - Amouyel, Philippe

AU - Arveiler, Dominique

AU - Basart, Hanneke

AU - Boehnke, Michael

AU - Boerwinkle, Eric

AU - Brambilla, Paolo

AU - Cambien, Francois

AU - Cupples, Adrienne L.

AU - De Faire, Ulf

AU - Dehghan, Abbas

AU - Diemert, Patrick

AU - Epstein, Stephen E.

AU - Evans, Alun

AU - Ferrario, Marco M.

AU - Ferrières, Jean

AU - Gauguier, Dominique

AU - Go, Alan S.

AU - Goodall, Alison H.

AU - Gudnason, Villi

AU - Hazen, Stanley L.

AU - Holm, Hilma

AU - Iribarren, Carlos

AU - Jang, Yangsoo

AU - Kähönen, Mika

AU - Kee, Frank

AU - Kim, Hyo Soo

AU - Klopp, Norman

AU - Koenig, Wolfgang

AU - Kratzer, Wolfgang

AU - Kuulasmaa, Kari

AU - Laakso, Markku

AU - Laaksonen, Reijo

AU - Lee, Ji Young

AU - Lind, Lars

AU - Ouwehand, Willem H.

AU - Parish, Sarah

AU - Park, Jeong E.

AU - Pedersen, Nancy L.

AU - Peters, Annette

AU - Quertermous, Thomas

AU - Rader, Daniel J.

AU - Salomaa, Veikko

AU - Schadt, Eric

AU - Shah, Svati H.

AU - Sinisalo, Juha

AU - Stark, Klaus

AU - Stefansson, Kari

AU - Trégouët, David Alexandre

AU - Virtamo, Jarmo

AU - Wallentin, Lars

AU - Wareham, Nicholas

AU - Zimmermann, Martina E.

AU - Nieminen, Markku S.

AU - Hengstenberg, Christian

AU - Sandhu, Manjinder S.

AU - Pastinen, Tomi

AU - Syvänen, Ann Christine

AU - Hovingh, G. Kees

AU - Dedoussis, George

AU - Franks, Paul W.

AU - Lehtimäki, Terho

AU - Metspalu, Andres

AU - Zalloua, Pierre A.

AU - Siegbahn, Agneta

AU - Schreiber, Stefan

AU - Ripatti, Samuli

AU - Blankenberg, Stefan S.

AU - Perola, Markus

AU - Clarke, Robert

AU - Boehm, Bernhard O.

AU - O'Donnell, Christopher

AU - Reilly, Muredach P.

AU - März, Winfried

AU - Collins, Rory

AU - Kathiresan, Sekar

AU - Hamsten, Anders

AU - Kooner, Jaspal S.

AU - Thorsteinsdottir, Unnur

AU - Danesh, John

AU - Palmer, Colin N.A.

AU - Roberts, Robert

AU - Watkins, Hugh

AU - Schunkert, Heribert

AU - Samani, Nilesh J.

PY - 2013/1/1

Y1 - 2013/1/1

N2 - 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 (r 2 < 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.

AB - 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 (r 2 < 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.

UR - https://www.scopus.com/pages/publications/84871969762

U2 - 10.1038/ng.2480

DO - 10.1038/ng.2480

M3 - Journal articles

C2 - 23202125

AN - SCOPUS:84871969762

SN - 1061-4036

VL - 45

SP - 25

EP - 33

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

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

Abstract

Funding

Research Areas and Centers

DFG Research Classification Scheme

UN SDGs

Access to Document

Other files and links

Fingerprint

EXC 306: Inflammation at Interfaces

Cite this

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

Abstract

Funding

Research Areas and Centers

DFG Research Classification Scheme

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

EXC 306: Inflammation at Interfaces

Cite this