Background: Genome-wide association studies have identified common variants modestly associated with coronary artery disease (CAD), which can be combined into genetic risk scores. We hypothesized that some individuals with early, severe CAD would have scores at the high end (>99^th percentile) of the distribution, thus identifying polygenic CAD as a novel inherited form of CAD.

Purpose: To determine the polygenic risk attributable to reported common variants in individuals with early, severe CAD and identify potential cases of polygenic CAD.

Methods: All individuals of European descent who underwent cardiac catheterization at the Hamilton Health Sciences Heart Investigation Unit between February and August 2014, had angiography proven CAD and were under the age of 40 for men and 45 for women were approached for participation in our study. Fourteen individuals consented to genetic analysis and were genotyped using the HumanCoreExome BeadChip (Illumina) with ensuing 1000 Genomes imputation. We calculated weighted genetic risk scores based on data from the CARDIoGRAMplusC4D Consortium, first with 45 single nucleotide polymorphisms (SNPs) reaching genome-wide significance (wGRS45) and subsequently with 144 SNPs associated with CAD at a false discovery rate of 5% (wGRS144). Genetic risk scores were compared to a distribution generated from the expected allele frequencies in the general population.

Findings: There was a significant enrichment in high wGRS45 and wGRS144 in the study population (p=0.0006 and 0.003, respectively). Two individuals had a wGRS45 above the 99^th percentile of the expected distribution (p=0.008, Figure 1). The individual with the highest score had higher than three-fold and five-fold increases in risk of CAD according to wGRS45 and wGRS144 respectively. This male individual had a quadruple coronary artery bypass graft surgery at age 38 and presented with a graft occlusion 12 years later. He had none of the traditional risk factors for CAD before the first event. The genetic risk scores remained above the 99^th percentile after excluding SNPs in loci associated with known risk factors.

Conclusions: These results suggest the existence of a polygenic form of CAD which could increase risk sufficiently to provoke premature events and emphasize the potential of genetic information for CAD risk assessment.

Keywords: Coronary artery disease, Genetic risk score, Risk assessment, Polygenic model