Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease
Tom R. Webb(University of Leicester), Jeanette Erdmann(Universität Hamburg), Kathleen Stirrups(Queen Mary University of London), Nathan O. Stitziel(James S. McDonnell Foundation), Nicholas G. D. Masca(University of Leicester), Henning Jansen(German Centre for Cardiovascular Research), Stavroula Kanoni(Queen Mary University of London), Christopher P. Nelson(University of Leicester), Paola G. Ferrario(German Centre for Cardiovascular Research), Inke R. König(German Centre for Cardiovascular Research), John D. Eicher(National Heart Lung and Blood Institute), Andrew D. Johnson(National Heart Lung and Blood Institute), Stephen E. Hamby(University of Leicester), Christer Betsholtz(Uppsala University), Arno Ruusalepp(Tartu University Hospital), Oscar Franzén(Clinical Gene Networks (Sweden)), Eric E. Schadt(Icahn School of Medicine at Mount Sinai), Johan Björkegren(Karolinska Institutet), Peter Weeke(University of Copenhagen), Paul L. Auer(University of Wisconsin–Milwaukee), Ursula M. Schick(Fred Hutch Cancer Center), Yingchang Lu(Icahn School of Medicine at Mount Sinai), He Zhang(University of Leicester), Marie‐Pierre Dubé(Montreal Heart Institute), Anuj Goel(Centre for Human Genetics), Martin Farrall(Centre for Human Genetics), Gina M. Peloso(Massachusetts General Hospital), Hong‐Hee Won(Massachusetts General Hospital), Ron Do(Icahn School of Medicine at Mount Sinai), Erik Van Iperen(Amsterdam UMC Location University of Amsterdam), Jochen Kruppa(University of Veterinary Medicine Hannover, Foundation), Anubha Mahajan(Centre for Human Genetics), Robert A. Scott(Addenbrooke's Hospital), Christina Willenborg(University of Lübeck), Peter S. Braund(University of Leicester), Julian C. van Capelleveen(Amsterdam UMC Location University of Amsterdam), Alex S. F. Doney(Ninewells Hospital), Louise A. Donnelly(Ninewells Hospital), Rosanna Asselta(Humanitas University), Pier Angelica Merlini(Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda), Stefano Duga(Humanitas University), Nicola Marziliano(Associazione Istituzione Libera Università Nuorese), Joshua C. Denny(Vanderbilt University Medical Center), Christian M. Shaffer(Vanderbilt University Medical Center), Nour Eddine El-Mokhtari(Institut für Berufliche Aus- und Fortbildung), André Franke(Christian-Albrechts-Universität zu Kiel), Stefanie Heilmann‐Heimbach(University of Michigan), Christian Hengstenberg(James S. McDonnell Foundation), Per Hoffmann(University of Bonn), Oddgeir L. Holmen(University of Michigan), Kristian Hveem(Levanger Hospital), Jan-Håkan Jansson(Skellefteå Hospital), Karl‐Heinz Jöckel(Institut für Medizinische Informatik, Biometrie und Epidemiologie), Thorsten Kessler(German Centre for Cardiovascular Research), Jennifer Kriebel(Helmholtz Zentrum München), Karl‐Ludwig Laugwitz(TUM Klinikum), Eirini Marouli(Queen Mary University of London), Nicola Martinelli(University of Verona), Mark I. McCarthy(Centre for Human Genetics), Natalie R. van Zuydam(University of Oxford), Christa Meisinger(Helmholtz Zentrum München), Tõnu Esko(Tartu University Hospital), Evelin Mihailov(University of Tartu), Stefan Andersson Escher(Lund University), Maris Alver(Estonian Biocentre), Susanne Moebus(Institut für Medizinische Informatik, Biometrie und Epidemiologie), Andrew D. Morris(National Heart Lung and Blood Institute), Jarma Virtamo(Finnish Institute for Health and Welfare), Majid Nikpay(University of Ottawa), Oliviero Olivieri(University of Verona), Sylvie Provost(Montreal Heart Institute), Alaa AlQarawi(King Abdulaziz University), Neil R. Robertson(Centre for Human Genetics), Karen O. Akinsansya(Merck & Co., Inc., Rahway, NJ, USA (United States)), Dermot F. Reilly(Merck & Co., Inc., Rahway, NJ, USA (United States)), Thomas Vogt(Merck & Co., Inc., Rahway, NJ, USA (United States)), Yin Wu(Merck & Co., Inc., Rahway, NJ, USA (United States)), Folkert W. Asselbergs(University of Michigan), Charles Kooperberg(University of Michigan), Rebecca D. Jackson(The Ohio State University), Eli A. Stahl(Icahn School of Medicine at Mount Sinai), Martina Müller‐Nurasyid(Helmholtz Zentrum München), Konstantin Strauch(Helmholtz Zentrum München), Tibor V. Varga(Lund University), Mélanie Waldenberger(Helmholtz Zentrum München), Lingyao Zeng(German Centre for Cardiovascular Research), Rajiv Chowdhury(University of Cambridge), Veikko Salomaa(University of Michigan), Ian Ford(University of Glasgow), J. Wouter Jukema(Leiden University Medical Center), Philippe Amouyel(Inserm), Jukka Kontto(Finnish Institute for Health and Welfare), Børge G. Nordestgaard(University of Copenhagen), Jean Ferrières(German Centre for Cardiovascular Research), Danish Saleheen(University of Pennsylvania), Naveed Sattar(University of Glasgow), Praveen Surendran(Ludwig-Maximilians-Universität München), Aline Wagner(Université de Strasbourg), Robin Young(University of Cambridge), Joanna M. M. Howson(University of Cambridge), Adam S. Butterworth(National Institute for Health and Care Research), John Danesh(Wellcome Sanger Institute), Diego Ardissino(University of Parma), Erwin P. Böttinger(Child Health and Development Institute), Raimund Erbel(Institut für Medizinische Informatik, Biometrie und Epidemiologie), Paul W. Franks(Lund University), Domenico Girelli(University of Verona), Alistair S. Hall(University of Leeds), G. Kees Hovingh(Amsterdam UMC Location University of Amsterdam), Adnan Kastrati(Deutsches Herzzentrum München), Wolfgang Lieb(University of Michigan), Thomas Meitinger(University of Leicester), William E. Kraus(Duke University), Svati H. Shah(Duke University), Ruth McPherson(University of Ottawa), Marju Orho‐Melander(Malmö University), Olle Melander(Lund University), Andres Metspalu(University of Michigan), Colin N.A. Palmer(Ninewells Hospital), Annette Peters(Helmholtz Zentrum München), Daniel J. Rader(Translational Therapeutics (United States)), Muredach P. Reilly, Ruth J. F. Loos(Child Health and Development Institute), Alex P. Reiner(Fred Hutch Cancer Center), Dan M. Roden(Vanderbilt University Medical Center), Jean‐Claude Tardif(Montreal Heart Institute), John R. Thompson(Glenfield Hospital), Nicholas J. Wareham(Addenbrooke's Hospital), Hugh Watkins(Centre for Human Genetics), Cristen J. Willer(University of Michigan), Nilesh J. Samani(University of Leicester), Heribert Schunkert(German Centre for Cardiovascular Research), Panos Deloukas(Queen Mary University of London), Sekar Kathiresan(Massachusetts General Hospital)
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Abstract
BACKGROUND: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. RESULTS: with a range of other diseases/traits. CONCLUSIONS: We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.
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