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

Authors:
Thomas R Webb Jeanette Erdmann Kathleen E Stirrups Nathan O Stitziel Nicholas G D Masca Henning Jansen Stavroula Kanoni Christopher P Nelson Paola G Ferrario Inke R König John D Eicher Andrew D Johnson Stephen E Hamby Christer Betsholtz Arno Ruusalepp Oscar Franzén Eric E Schadt Johan L M Björkegren Peter E Weeke Paul L Auer Ursula M Schick Yingchang Lu He Zhang Marie-Pierre Dube Anuj Goel Martin Farrall Gina M Peloso Hong-Hee Won Ron Do Erik van Iperen Jochen Kruppa Anubha Mahajan Robert A Scott Christina Willenborg Peter S Braund Julian C van Capelleveen Alex S F Doney Louise A Donnelly Rosanna Asselta Pier A Merlini Stefano Duga Nicola Marziliano Josh C Denny Christian Shaffer Nour Eddine El-Mokhtari Andre Franke Stefanie Heilmann Christian Hengstenberg Per Hoffmann Oddgeir L Holmen Kristian Hveem Jan-Håkan Jansson Karl-Heinz Jöckel Thorsten Kessler Jennifer Kriebel Karl L Laugwitz Eirini Marouli Nicola Martinelli Mark I McCarthy Natalie R Van Zuydam Christa Meisinger Tõnu Esko Evelin Mihailov Stefan A Escher Maris Alver Susanne Moebus Andrew D Morris Jarma Virtamo Majid Nikpay Oliviero Olivieri Sylvie Provost Alaa AlQarawi Neil R Robertson Karen O Akinsansya Dermot F Reilly Thomas F Vogt Wu Yin Folkert W Asselbergs Charles Kooperberg Rebecca D Jackson Eli Stahl Martina Müller-Nurasyid Konstantin Strauch Tibor V Varga Melanie Waldenberger Lingyao Zeng Rajiv Chowdhury Veikko Salomaa Ian Ford J Wouter Jukema Philippe Amouyel Jukka Kontto Børge G Nordestgaard Jean Ferrières Danish Saleheen Naveed Sattar Praveen Surendran Aline Wagner Robin Young Joanna M M Howson Adam S Butterworth John Danesh Diego Ardissino Erwin P Bottinger Raimund Erbel Paul W Franks Domenico Girelli Alistair S Hall G Kees Hovingh Adnan Kastrati Wolfgang Lieb Thomas Meitinger William E Kraus Svati H Shah Ruth McPherson Marju Orho-Melander Olle Melander Andres Metspalu Colin N A Palmer Annette Peters Daniel J Rader Muredach P Reilly Ruth J F Loos Alex P Reiner Dan M Roden Jean-Claude Tardif John R Thompson Nicholas J Wareham Hugh Watkins Cristen J Willer Nilesh J Samani Heribert Schunkert Panos Deloukas Sekar Kathiresan

J Am Coll Cardiol 2017 Feb;69(7):823-836

Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts.

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 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.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2016.11.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5314135PMC
February 2017
173 Reads

Publication Analysis

Top Keywords

cad loci
16
loci associated
16
identified loci
12
cad
10
loci
9
single nucleotide
8
nucleotide polymorphisms
8
genome-wide association
8
risk allele
8
cardiovascular risk
8
control subjects
8
cad genome-wide
8
genome-wide significance
8
associated cad
8
association
6
associated
6
pleiotropy
5
risk
5
statistical association
4
association signals
4

Similar Publications