Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease
Open Access
- 2 February 2018
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation Research
- Vol. 122 (3), 433-443
- https://doi.org/10.1161/circresaha.117.312086
Abstract
Rationale: Coronary artery disease (CAD) is a complex phenotype driven by genetic and environmental factors. 97 genetic risk loci have been identified so far, but the identification of additional susceptibility loci might be important to enhance our understanding of the genetic architecture of CAD. Objective: To expand the number of genome-wide significant loci, catalog functional insights, and enhance our understanding of the genetic architecture of CAD. Methods and Results: We performed a genome-wide association study (GWAS) in 34,541 CAD cases and 261,984 controls of UK biobank Resource followed by replication in 88,192 cases and 162,544 controls from CARDIoGRAMplusC4D. We identified 75 loci that replicated and were genome-wide significant (P-8) in meta-analysis, 13 of which had not been reported previously. Next, to further identify novel loci we identified all promising (P-8) in meta-analysis. Finally, we performed a genome wide meta-analysis of all available data revealing 30 additional novel loci (P-8) without further replication. The increase in sample size by UK Biobank raised the number of reconstituted gene-sets from 4.2% to 13.9% of all gene-sets to be involved in CAD. For the 64 novel loci, 155 candidate causal genes were prioritized, many without an obvious connection to CAD. Fine-mapping of the 161 CAD loci generated lists of credible sets of single causal variants and genes for functional follow-up. Genetic risk variants of CAD were linked to development of atrial fibrillation, heart failure and death. Conclusions: We identified 64 novel genetic risk loci for CAD and performed fine-mapping of all 161 risk loci to obtain a credible set of causal variants. The large expansion of reconstituted gene-sets argues in favor of an expanded "omnigenic model" view on the genetic architecture of CAD.Keywords
This publication has 29 references indexed in Scilit:
- Association analyses based on false discovery rate implicate new loci for coronary artery diseaseNature Genetics, 2017
- Identification of 15 novel risk loci for coronary artery disease and genetic risk of recurrent events, atrial fibrillation and heart failureScientific Reports, 2017
- Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanismsNature Genetics, 2017
- Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015The Lancet, 2016
- A comprehensive 1000 Genomes–based genome-wide association meta-analysis of coronary artery diseaseNature Genetics, 2015
- Large-scale association analysis identifies new risk loci for coronary artery diseaseNature Genetics, 2012
- Large-scale association analysis identifies 13 new susceptibility loci for coronary artery diseaseNature Genetics, 2011
- Genomewide Association Analysis of Coronary Artery DiseaseThe New England Journal of Medicine, 2007
- A Common Variant on Chromosome 9p21 Affects the Risk of Myocardial InfarctionScience, 2007
- A Common Allele on Chromosome 9 Associated with Coronary Heart DiseaseScience, 2007