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

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posted on 2017-03-28, 14:47 authored by Thomas R. Webb, J. Erdmann, K. E. Stirrups, N. O. Stitziel, N. G. Masca, H. Jansen, S. Kanoni, C. P. Nelson, P. G. Ferrario, I. R. König, J. D. Eicher, A. D. Johnson, S. E. Hamby, C. Betsholtz, A. Ruusalepp, O. Franzén, E. E. Schadt, J. L. Björkegren, P. E. Weeke, P. L. Auer, U. M. Schick, Y. Lu, H. Zhang, M. P. Dube, A. Goel, M. Farrall, G. M. Peloso, H. H. Won, R. Do, E. van Iperen, J. Kruppa, A. Mahajan, R. A. Scott, C. Willenborg, P. S. Braund, J. C. van Capelleveen, A. S. Doney, L. A. Donnelly, R. Asselta, P. A. Merlini, S. Duga, N. Marziliano, J. C. Denny, C. Shaffer, N. E. El-Mokhtari, A. Franke, S. Heilmann, C. Hengstenberg, P. Hoffmann, O. L. Holmen, K. Hveem, J. H. Jansson, K. H. Jöckel, T. Kessler, J. Kriebel, K. L. Laugwitz, E. Marouli, N. Martinelli, M. I. McCarthy, N. R. Van Zuydam, C. Meisinger, T. Esko, E. Mihailov, S. A. Escher, M. Alver, S. Moebus, A. D. Morris, J. Virtamo, M. Nikpay, O. Olivieri, S. Provost, A. AlQarawi, N. R. Robertson, K. O. Akinsansya, D. F. Reilly, T. F. Vogt, W. Yin, F. W. Asselbergs, C. Kooperberg, R. D. Jackson, E. Stahl, M. Müller-Nurasyid, K. Strauch, T. V. Varga, M. Waldenberger, Wellcome Trust Case Control Consortium, L. Zeng, R. Chowdhury, V. Salomaa, I. Ford, J. W. Jukema, P. Amouyel, J. Kontto, MORGAM Investigators, B. G. Nordestgaard, J. Ferrières, D. Saleheen, N. Sattar, P. Surendran, A. Wagner, R. Young, J. M. Howson, A. S. Butterworth, J. Danesh, D. Ardissino, E. P. Bottinger, R. Erbel, P. W. Franks, D. Girelli, A. S. Hall, G. K. Hovingh, A. Kastrati, W. Lieb, T. Meitinger, W. E. Kraus, S. H. Shah, R. McPherson, M. Orho-Melander, O. Melander, A. Metspalu, C. N. Palmer, A. Peters, D. J. Rader, M. P. Reilly, R. J. Loos, A. P. Reiner, D. M. Roden, J. C. Tardif, J. R. Thompson, N. J. Wareham, H. Watkins, C. J. Willer, Nilesh J. Samani, H. Schunkert, P. Deloukas, S. Kathiresan, Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators
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.

History

Citation

Journal of the American College of Cardiology, 2017, 69 (7), pp. 823-836

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cardiovascular Sciences

Version

  • VoR (Version of Record)

Published in

Journal of the American College of Cardiology

issn

0735-1097

eissn

1558-3597

Acceptance date

2017-11-17

Copyright date

2017

Available date

2017-03-28

Publisher version

http://www.sciencedirect.com/science/article/pii/S0735109716373417

Language

en

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