Advanced

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

Webb, Thomas R.; Erdmann, Jeanette; Stirrups, Kathleen E.; Stitziel, Nathan O.; Masca, Nicholas G D; Jansen, Henning; Kanoni, Stavroula; Nelson, Christopher P; Ferrario, Paola G. and König, Inke R., et al. (2017) In Journal of the American College of Cardiology 69(7). p.823-836
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cholesteryl ester transfer protein, expression quantitative trait loci, genetics, genome-wide association, single nucleotide polymorphism
in
Journal of the American College of Cardiology
volume
69
issue
7
pages
14 pages
publisher
Elsevier USA
external identifiers
  • scopus:85013005062
  • wos:000396340400009
ISSN
0735-1097
DOI
10.1016/j.jacc.2016.11.056
language
English
LU publication?
yes
id
ffd68d88-5a74-4c0d-aa04-94d31fdc9d79
date added to LUP
2017-03-03 07:30:29
date last changed
2018-05-27 04:40:20
@article{ffd68d88-5a74-4c0d-aa04-94d31fdc9d79,
  abstract     = {<p>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 &gt;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 &lt; 1 × 10<sup>−4</sup> 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.</p>},
  author       = {Webb, Thomas R. and Erdmann, Jeanette and Stirrups, Kathleen E. and Stitziel, Nathan O. and Masca, Nicholas G D and Jansen, Henning and Kanoni, Stavroula and Nelson, Christopher P and Ferrario, Paola G. and König, Inke R. and Eicher, John D. and Johnson, Andrew D and Hamby, Stephen E. and Betsholtz, Christer and Ruusalepp, Arno and Franzén, Oscar and Schadt, Eric and Björkegren, Johan L M and Weeke, Peter E. and Auer, Paul L. and Schick, Ursula M and Lu, Yingchang and Zhang, He and Dube, Marie Pierre and Goel, Anuj and Farrall, Martin and Peloso, Gina M. and Won, Hong-Hee and Do, Ron and van Iperen, Erik Pa and Kruppa, Jochen and Mahajan, Anubha and Scott, Robert A. and Willenborg, Christina and Braund, Peter S. and Van Capelleveen, Julian C. and Doney, Alex S F and Donnelly, Louise A and Asselta, Rosanna and Merlini, Pier Angelica and Duga, Stefano and Marziliano, Nicola and Denny, Josh C and Shaffer, Christian M. and El Mokhtari, Nour Eddine and Franke, Andre and Heilmann, Stefanie and Hengstenberg, Christian and Hoffmann, Per and Holmen, Oddgeir L. and Hveem, Kristian and Jansson, Jan-Håkan and Jöckel, Karl-Heinz and Kessler, Thorsten and Kriebel, Jennifer and Laugwitz, Karl L. and Marouli, Eirini and Martinelli, Nicola and McCarthy, Mark I. and van Zuydam, Natalie R. and Meisinger, Christa and Esko, Tõnu and Mihailov, Evelin and Escher, Stefan A and Alver, Maris and Moebus, Susanne and Morris, Andrew D. and Virtamo, Jarma and Nikpay, Majid and Olivieri, Oliviero and Provost, Sylvie and AlQarawi, Alaa and Robertson, Neil R and Akinsansya, Karen O. and Reilly, Dermot F and Vogt, Thomas F. and Yin, Wu and Asselbergs, Folkert W and Kooperberg, Charles and Jackson, Rebecca D. and Stahl, Eli A and Müller-Nurasyid, Martina and Strauch, Konstantin and Varga, Tibor V. and Waldenberger, Melanie and Zeng, Lingyao and Chowdhury, Rajiv and Salomaa, Veikko and Ford, Ian and Jukema, J. Wouter and Amouyel, Philippe and Kontto, Jukka and Nordestgaard, Børge G and Ferrières, Jean and Saleheen, Danish and Sattar, Naveed and Surendran, Praveen and Wagner, Aline and Young, Robin and Howson, Joanna M. M. and Butterworth, Adam S. and Danesh, John and Ardissino, Diego and Bottinger, Erwin P and Erbel, Raimund and Franks, Paul W. and Girelli, Domenico and Hall, Alistair S and Hovingh, G. Kees and Kastrati, Adnan and Lieb, Wolfgang and Meitinger, Thomas and Kraus, William E and Shah, Svati H and McPherson, Ruth and Orho-Melander, Marju and Melander, Olle and Metspalu, Andres and Palmer, Colin N. A. and Peters, Annette and Rader, Daniel J. and Reilly, Muredach P. and Loos, Ruth J F and Reiner, Alex P and Roden, Dan M and Tardif, Jean-Claude and Thompson, John R. and Wareham, Nicholas J and Watkins, Hugh and Willer, Cristen J. and Samani, Nilesh J. and Schunkert, Heribert and Deloukas, Panos and Kathiresan, Sekar},
  issn         = {0735-1097},
  keyword      = {cholesteryl ester transfer protein,expression quantitative trait loci,genetics,genome-wide association,single nucleotide polymorphism},
  language     = {eng},
  month        = {02},
  number       = {7},
  pages        = {823--836},
  publisher    = {Elsevier USA},
  series       = {Journal of the American College of Cardiology},
  title        = {Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease},
  url          = {http://dx.doi.org/10.1016/j.jacc.2016.11.056},
  volume       = {69},
  year         = {2017},
}