Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease

Webb TR, Erdmann J, Stirrups KE, Stitziel NO, Masca NGD, Jansen H, Kanoni S, Nelson CP, Ferrario PG, Koenig IR, Eicher JD, Johnson AD, Hamby SE, Betsholtz C, Ruusalepp A, Franzen O, Schadt EE, Bjoerkegren JLM, Weeke PE, Auer PL, Schick UM, Lu Y, Zhang H, Dube MP, Goel A, Farrall M, Peloso GM, Won HH, Do R, Van Iperen E, Kruppa J, Mahajan A, Scott RA, Willenborg C, Braund PS, Van Capelleveen JC, Doney ASF, Donnelly LA, Asselta R, Merlini PA, Duga S, Marziliano N, Denny JC, Shaffer C, El-Mokhtari NE, Franke A, Heilmann S, Hengstenberg C, Hoffmann P, Holmen OL, Hveem K, Jansson JH, Joeckel KH, Kessler T, Kriebel J, Laugwitz KL, Marouli E, Martinelli N, Mccarthy MI, Van Zuydam NR, Meisinger C, Esko T, Mihailov E, Escher SA, Alver M, Moebus S, Morris AD, Virtamo J, Nikpay M, Olivieri O, Provost S, Alqarawi A, Robertson NR, Akinsansya KO, Reilly DF, Vogt TF, Yin W, Asselbergs FW, Kooperberg C, Jackson RD, Stahl E, Mueller-Nurasyid M, Strauch K, Varga TV, Waldenberger M, Zeng L, Chowdhury R, Salomaa V, Ford I, Jukema JW, Amouyel P, Kontto J, Nordestgaard BG, Ferrieres J, Saleheen D, Sattar N, Surendran P, Wagner A, Young R, Howson JMM, Butterworth AS, Danesh J, Ardissino D, Bottinger EP, Erbel R, Franks PW, Girelli D, Hall AS, Hovingh GK, Kastrati A, Lieb W, Meitinger T, Kraus WE, Shah SH, Mcpherson R, Orho-Melander M, Melander O, Metspalu A, Palmer CNA, Peters A, Rader DJ, Reilly MP, Loos RJF, Reiner AP, Roden DM, Tardif JC, Thompson JR, Wareham NJ, Watkins H, Willer CJ, Samani NJ, Schunkert H, Deloukas P, Kathiresan S (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Book Volume: 69

Pages Range: 823-836

Journal Issue: 7

DOI: 10.1016/j.jacc.2016.11.056

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 We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10⁻⁴ 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.

Involved external institutions

Massachusetts General Hospital United States (USA) (US) Icahn School of Medicine at Mount Sinai United States (USA) (US) University of Tartu Estonia (EE) Lund University / Lunds universitet Sweden (SE) University of Oxford United Kingdom (GB) University of Cambridge United Kingdom (GB) Azienda Ospedaliero-Universitaria di Parma / Parma University Hospital Italy (IT) Universitätsklinikum Essen Germany (DE) University of Verona / Università degli Studi di Verona Italy (IT) University of Leeds United Kingdom (GB) Academic Medical Centre / Academisch Medisch Centrum (AMC) Netherlands (NL) Technische Universität München (TUM) Germany (DE) Christian-Albrechts-Universität zu Kiel Germany (DE) Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK e.V.) Germany (DE) Duke University United States (USA) (US) University of Dundee United Kingdom (GB) University of Pennsylvania United States (USA) (US) Columbia University United States (USA) (US) Vanderbilt University United States (USA) (US) Université de Montréal Canada (CA) Glenfield Hospital United Kingdom (GB) Addenbrooke's Hospital United Kingdom (GB) University of Leicester United Kingdom (GB) Ospedale San Francesco Italy (IT) University of Ottawa Canada (CA) Universität zu Lübeck Germany (DE) Queen Mary, University of London United Kingdom (GB) Washington University United States (USA) (US) US National Institutes of Health (NIH) United States (USA) (US) Uppsala University Sweden (SE) Clinical Gene Networks (Sweden) Sweden (SE) Karolinska Institute Sweden (SE) University of Wisconsin - Madison United States (USA) (US) Fred Hutchinson Cancer Research Center United States (USA) (US) University of Michigan United States (USA) (US) Stiftung Tierärztliche Hochschule Hannover (TiHo) Germany (DE) Istituto Clinico Humanitas Italy (IT) Ospedale Niguarda Ca' Granda / ASST Grande Ospedale Metropolitano Niguarda Italy (IT) imland Klinik Rendsburg Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) NTNU Trondheim - Norwegian University of Science and Technology Norway (NO) Umeå University Sweden (SE) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich Germany (DE) University of Edinburgh United Kingdom (GB) National Institute for Health and Welfare (THL) Finland (FI) King Abdulaziz University (KAU) / جامعة الملك عبد العزيز Saudi Arabia (SA) Merck & Co., Inc. / Merck Sharp & Dohme Corp (MSD) United States (USA) (US) University Medical Centre Utrecht (UMC Utrecht) Netherlands (NL) Ohio State University United States (USA) (US) University of Glasgow United Kingdom (GB) Leiden University Netherlands (NL) LILLE 1 University - Science and Technology France (FR) University of Copenhagen Denmark (DK) Université Fédérale de Toulouse Midi-Pyrénées France (FR) Ludwig-Maximilians-Universität (LMU) Germany (DE) Université de Strasbourg (UDS) France (FR)

How to cite

APA:

Webb, T.R., Erdmann, J., Stirrups, K.E., Stitziel, N.O., Masca, N.G.D., Jansen, H.,... Kathiresan, S. (2017). Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease. Journal of the American College of Cardiology, 69(7), 823-836. https://doi.org/10.1016/j.jacc.2016.11.056

MLA:

Webb, Thomas R., et al. "Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease." Journal of the American College of Cardiology 69.7 (2017): 823-836.

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