Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Abstract

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10^-8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

Figure 1

Schematic of the study design. The sample-size information is provided as number of cases/number of controls. Note, samples with de novo genotyping that were also in the CARDIoGRAMplusC4D study were removed prior to meta-analysis.* 1,826 CAD cases and 449 controls from EPIC-CVD with de novo genotyping were also included in CARDIoGRAMplusC4D and were therefore excluded from the larger meta-analysis. The actual number of EUR individuals contributed to the meta-analysis of our studies with de novo genotyping and CARDIoGRAMplusC4D was 14,267 CAD cases and 16,167 controls.†3,704 CAD cases and 3,433 controls from PROMIS with de novo genotyping were also included in CARDIoGRAMplusC4D and were therefore excluded from the larger meta-analysis. The actual number of SAS samples contributed to the meta-analysis of our studies with de novo genotyping and CARDIoGRAMplusC4D was 3,950 CAD cases and 3,581 controls.

Figure 2

Plot showing the association of ~79,000 variants with CAD (-log₁₀P-value) in up to 88,192 cases and 162,544 controls from the all ancestry fixed effects meta-analysis. SNPs are ordered in physical position. No adjustments to P-values to account for multiple testing have been made. The outer track represents the chromosomal number. Blue dots represent known loci and red dots are the new loci identified in the current study. Each association peak is labeled with the name of the closest gene(s) to the sentinel SNP. GWAS significance (-log₁₀(P) ~ 7.3).