Abstract 15963: Toward Development of a Genetic Risk Score for Sudden Cardiac Death

Introduction: Genome-wide association studies have identified multiple common variants associated with risk of SCD. However, independently these loci make modest contributions to disease risk. The objective of this study was to develop a genetic risk score (GRS) for SCD to evaluate the cumulative effects of these variants on SCD risk. Methods: We identified variants with established associations to SCD (14 SNPs). To these we added SNPs associated with intermediate phenotypes of SCD including those involved in cardiac ventricular conduction (QRS duration, 26 SNPs), repolarization (QT interval, 9 SNPs) and heart rate (18 SNPs). After quality control, a total of 67 SNPs were investigated. The GRS was calculated using the weighted approach based on the number of risk alleles weighted by the beta coefficients derived from the original studies. GRSs were tested for association using logistic regression models. A total of 966 cases from an ongoing prospective community-based evaluation of SCD in a large U.S. community and 1,926 subjects with coronary artery disease (CAD) from the Wellcome Trust Case Control Consortium (WTCCC+) were included in this study. Results: The highest increased risk of SCD was observed with the combination of two previously associated SCD SNPs, rs3010396 within CASQ2 and rs6730157 within RAB3GAP1 (OR= 2.43 [1.8-3.2], P=7.41x10 -10 ). CASQ2 and RAB3GAP1 have been previously implicated in calcium signaling and heart disease. Modest associations were found for a GRS composed of 14 SCD SNPs (OR=1.17 [1.05-1.29], P= 0.002). The results remained significant after adjusting for multiple testing. We did not observe significant associations for SNPs linked to the other investigated traits, for individual loci or the overall combined risk score. Conclusions: These findings suggest that the cumulative effects of SCD-associated gene variants may contribute to improved SCD prediction. Additional studies of cumulative genetic risk in larger, well-phenotyped populations are warranted.