In silico genome-wide gene-based association analysis reveals new genes predisposing to coronary artery disease

Genome-wide association study (GWAS) have identified more than 300 single nucleotide polymorphisms at 163 independent loci associated with coronary artery disease (CAD). However, there is no full understanding about the causal genes for CAD and the mechanisms of their action. We aimed to perform a post GWAS analysis to identify genes whose polymorphism may influence the risk of CAD. Using the UK Biobank GWAS summary statistics, we performed a gene-based association analysis. We found 63 genes significantly associated with CAD due to their within-gene polymorphisms. Many of these genes are well known. Some known CAD genes such as FURIN and SORT1 did not show the gene-based association because their variants had low GWAS signals or gene-based association was inflated by the strong GWAS signal outside the gene. For several known CAD genes, we demonstrated that their effects could be explained not only or not at all by their own variants but by the variants within the neighboring genes controlling their expression. Using several bioinformatics techniques, we suggested potential mechanisms underlying gene-CAD associations. Three genes, CDK19, NCALD, and ARHGEF12 were not previously associated with CAD. The role of these genes should be clarified in further studies.