Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants.

Background: Genome-wide association studies have identified several hundred susceptibility single nucleotide variants for coronary artery disease (CAD). Despite single nucleotide variant-based genome-wide association studies improving our understanding of the genetics of CAD, the contribution of structural variants (SVs) to the risk of CAD remains largely unclear.

Method And Results: We leveraged SVs detected from high-coverage whole genome sequencing data in a diverse group of participants from the National Heart Lung and Blood Institute's Trans-Omics for Precision Medicine program. Single variant tests were performed on 58 706 SVs in a study sample of 11 556 CAD cases and 42 907 controls. Additionally, aggregate tests using sliding windows were performed to examine rare SVs. One genome-wide significant association was identified for a common biallelic intergenic duplication on chromosome 6q21 (=1.54E-09, odds ratio=1.34). The sliding window-based aggregate tests found 1 region on chromosome 17q25.3, overlapping , to be significantly associated with coronary artery disease (=1.03E-10). is highly expressed in arterial and adipose tissues while broadly affecting several cardiometabolic traits.

Conclusions: Our results suggest that SVs, both common and rare, may influence the risk of coronary artery disease.