Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium

Abbas Dehghan, Joshua C Bis, Charles C White, Albert Vernon Smith, Alanna C Morrison, L Adrienne Cupples, Stella Trompet, Daniel I Chasman, Thomas Lumley, Uwe Völker, Brendan M Buckley, Jingzhong Ding, Majken K Jensen, Aaron R Folsom, Stephen B Kritchevsky, Cynthia J Girman, Ian Ford, Marcus Dörr, Veikko Salomaa, André G UitterlindenGudny Eiriksdottir, Ramachandran S Vasan, Nora Franceschini, Cara L Carty, Jarmo Virtamo, Serkalem Demissie, Philippe Amouyel, Dominique Arveiler, Susan R Heckbert, Jean Ferrières, Pierre Ducimetière, Nicholas L Smith, Ying A Wang, David S Siscovick, Kenneth M Rice, Per-Gunnar Wiklund, Kent D Taylor, Alun Evans, Frank Kee, Jerome I Rotter, Juha Karvanen, Kari Kuulasmaa, Gerardo Heiss, Peter Kraft, Lenore J Launer, Albert Hofman, Marcello R P Markus, Lynda M Rose, Kaisa Silander, Peter Wagner, Emelia J Benjamin, Kurt Lohman, David J Stott, Fernando Rivadeneira, Tamara B Harris, Daniel Levy, Yongmei Liu, Eric B Rimm, J Wouter Jukema, Henry Völzke, Paul M Ridker, Stefan Blankenberg, Oscar H Franco, Vilmundur Gudnason, Bruce M Psaty, Eric Boerwinkle, Christopher J O'Donnell

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Abstract

Background: Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting. Methods: We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up. Results: In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3). Conclusions: QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.
Original languageEnglish
Pages (from-to)e0144997
JournalPloS one
Volume11
Issue number3
DOIs
Publication statusPublished - 07 Mar 2016

Keywords

  • Aged
  • Cohort Studies
  • Cooperative Behavior
  • Coronary Artery Disease
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Male
  • Middle Aged
  • Myocardial Infarction
  • Polymorphism, Single Nucleotide
  • Prospective Studies
  • Journal Article
  • Research Support, Non-U.S. Gov't

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