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

Author:
  • 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 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 Pa 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 Angelica Merlini
  • Stefano Duga
  • Nicola Marziliano
  • Josh C Denny
  • Christian M. 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 A 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
Publishing year: 2017-02-21
Language: English
Pages: 823-836
Publication/Series: Journal of the American College of Cardiology
Volume: 69
Issue: 7
Document type: Journal article
Publisher: Elsevier USA

Abstract english

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.

Keywords

  • Cardiac and Cardiovascular Systems
  • cholesteryl ester transfer protein
  • expression quantitative trait loci
  • genetics
  • genome-wide association
  • single nucleotide polymorphism

Other

Published
  • Genetic and Molecular Epidemiology
  • Diabetes and cardiovascular disease - genetic epidemiolgy
  • Hypertension and Cardiovascular Disease
  • ISSN: 0735-1097
Paul Franks
E-mail: paul.franks [at] med.lu.se

Principal investigator

Genetic and Molecular Epidemiology

+46 40 39 11 49

60-12-021

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