A comprehensive 1000 Genomes–based genome-wide association meta-analysis of coronary artery disease
Top Cited Papers
Open Access
- 7 September 2015
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Genetics
- Vol. 47 (10), 1121-1130
- https://doi.org/10.1038/ng.3396
Abstract
Hugh Watkins, Sekar Kathiresan, Ruth McPherson, Martin Farrall and colleagues report the results of a large genome-wide association meta-analysis of coronary artery disease based on 1000 Genomes imputation. They identify ten new risk loci and show that susceptibility to this disease is largely determined by common SNPs with small effect sizes. Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.Keywords
This publication has 84 references indexed in Scilit:
- An integrated map of genetic variation from 1,092 human genomesNature, 2012
- An integrated encyclopedia of DNA elements in the human genomeNature, 2012
- Genomic inflation factors under polygenic inheritanceEuropean Journal of Human Genetics, 2011
- Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studiesThe Lancet, 2011
- GCTA: A Tool for Genome-wide Complex Trait AnalysisAmerican Journal of Human Genetics, 2011
- Common vs. rare allele hypotheses for complex diseasesCurrent Opinion in Genetics & Development, 2009
- Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controlsNature, 2007
- Quantifying heterogeneity in a meta-analysisStatistics in Medicine, 2002
- Identification of a factor that links apoptotic cells to phagocytesNature, 2002
- Meta-analysis in clinical trialsControlled Clinical Trials, 1986