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Rationale: Although affecting different arterial territories, the related atherosclerotic vascular diseases coronary artery disease (CAD) and peripheral artery disease (PAD) share similar risk factors and have shared pathobiology. Analysis of their shared genetic architecture, along with that of common risk factors, may identify novel common biology. Objective: To identify novel pleiotropic genetic loci associated with atherosclerosis and provide a better understanding of biological pathways underlying atherosclerosis. Methods and Results: Summary statistics from genome wide association studies (GWAS) of nine known atherosclerotic (CAD, PAD) or atherosclerosis risk factors (body mass index, smoking initiation, type 2 diabetes, low density lipoprotein (LDL), high density lipoprotein, total cholesterol, and triglycerides) were combined to perform 15 separate multi-trait genetic association scans which resulted in 31 unique novel pleiotropic loci not yet reported as genome-wide significant for their respective traits. Colocalization with single-tissue eQTLs identified 34 candidate causal genes across 14 of the detected signals. Notably, the signal between PAD and CAD at the VDAC2 locus (rs7088974) colocalized with VDAC2 expression in aorta and tibial artery tissues. Additionally, the signal between PAD and LDL at the PCSK6 locus (rs1531817) affects PCSK6 splicing in human liver tissue and induced pluripotent derived hepatocyte like cells. Conclusions: Joint analysis of related atherosclerotic disease traits and their risk factors allowed identification of unified biology that may offer the opportunity for therapeutic manipulation. VDAC2 and PCSK6 represent possible shared causal biology where existing inhibitors may be able to be leveraged for novel therapies.

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