Abstract
Coronary artery disease (CAD) genome-wide association studies typically focus on single nucleotide variants (SNVs), and many potentially associated SNVs fail to reach the GWAS significance threshold. We performed gene and pathway-based association (GBA) tests on publicly available Coronary ARtery DIsease Genome wide Replication and Meta-analysis consortium Exome (n = 120,575) and multi ancestry pan UK Biobank study (n = 442,574) summary data using versatile gene-based association study (VEGAS2) and Multi-marker analysis of genomic annotation (MAGMA) to identify novel genes and pathways associated with CAD. We included only exonic SNVs and excluded regulatory regions. VEGAS2 and MAGMA ranked genes and pathways based on aggregated SNV test statistics. We used Bonferroni corrected gene and pathway significance threshold at 3.0 × 10–6 and 1.0 × 10–5, respectively. We also report the top one percent of ranked genes and pathways. We identified 17 top enriched genes with four genes (PCSK9, FAM177, LPL, ARGEF26), reaching statistical significance (p ≤ 3.0 × 10–6) using both GBA tests in two GWAS studies. In addition, our analyses identified ten genes (DUSP13, KCNJ11, CD300LF/RAB37, SLCO1B1, LRRFIP1, QSER1, UBR2, MOB3C, MST1R, and ABCC8) with previously unreported associations with CAD, although none of the single SNV associations within the genes were genome-wide significant. Among the top 1% non-lipid pathways, we detected pathways regulating coagulation, inflammation, neuronal aging, and wound healing.
Highlights
The CGEX summary data includes 120,575 (42,335 cases and 78,240 controls) individuals recruited from 20 studies across Europe and North America[1]
While there was some heterogeneity in the CAD definition across the study cohorts, the case definition for CAD can be summarized as the presence of one or more of the following: a history of myocardial infarction (MI); the presence of stable or unstable angina; a history of percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG); at least one epicardial coronary artery stenosis (> 50%) in coronary angiogram; International Classification of Disease (ICD-9 or 10) codes compatible with MI or PCI or CABG or chronic ischemic heart disease; abnormal myocardial stress imaging or died due to CAD
SNVs with non-heterogeneous effects (Cochran heterogeneity test p-value > 0.1) with association p-values below our genome-wide significant threshold (p < 5.0 × 1 0–8) were considered to be significantly associated with CAD in the CGEX data
Summary
This study aims to identify genes associated with CAD using results from non-synonymous autosomal genetic variants in the CARDIoGRAM Exome studies (CGEX) with VEGAS2 and further compare with MAGMA19
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