Large-scale association analysis identifies new risk loci for coronary artery disease

Abstract

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.

Figure 1

Canonical pathway analysis. (a) The four most significant canonical pathways represented in networks 3, 5 and 9, and overlapping networks ON1 (includes networks 1, 2, 6 and 8) and ON2 (includes networks 4 and 7); all molecules are listed by network in supplementary table 10. (b) Schematic showing parts of the atherosclerosis signaling, LXR/RXR activation and acute phase response signaling canonical pathways (Ingenuity) that are involved in both lipid metabolism and inflammation. Genes in confirmed CAD susceptibility loci (including both previously and newly reported) and in loci showing suggestive association with an FDR of <10% are depicted as black and gray ovals, respectively. Other key genes are depicted as white ovals; notably, some of them, such as IL1F10-IL1B, STAT3 and HMGCR, have SNPs ranking in the top 1,000 in the FDR analysis. The process leading to myocardial infarction involves multiple cell types that are depicted in this schematic as a composite cell (large oval) and its nucleus (inner oval) in the extracellular space; the smooth muscle cell is shown separately (SMC; red oval), whereas the blue oval depicts cell types involved in the inflammatory response.