The causal pathways of these pleiotropic genetic variants with CAD have yet to be elucidated. Many associated SNVs are in linkage disequilibrium (LD) with existing genetic variants, have pleiotropic effects, and are involved in overlapping pathways 6, 7. While much work to understand the effect of various environmental factors was undertaken in the past century, recent genome-wide association studies (GWAS) have identified multiple genetic loci associated with CAD 4, 5.Īlthough GWAS has identified more than 160 loci with one or more Single Nucleotide Variants (SNVs) significantly associated with CAD risk, many are in non-coding and intergenic regions with unknown functional significance 3, 6. Similar content being viewed by othersĬoronary artery disease (CAD) is a complex disease phenotype influenced by numerous genotypic (polygenic) and environmental factors 1, 2, 3. Among the top 1% non-lipid pathways, we detected pathways regulating coagulation, inflammation, neuronal aging, and wound healing. 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. 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. We also report the top one percent of ranked genes and pathways. We used Bonferroni corrected gene and pathway significance threshold at 3.0 × 10 –6 and 1.0 × 10 –5, respectively. VEGAS2 and MAGMA ranked genes and pathways based on aggregated SNV test statistics. We included only exonic SNVs and excluded regulatory regions. 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. 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.
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