AUTHOR=Bellomo Tiffany R. , Bone William P. , Chen Brian Y. , Gawronski Katerina A. B. , Zhang David , Park Joseph , Levin Michael , Tsao Noah , Klarin Derek , Lynch Julie , Assimes Themistocles L. , Gaziano J. Michael , Wilson Peter W. , Cho Kelly , Vujkovic Marijana , the VA Million Veteran Program , O’Donnell Christopher J. , Chang Kyong-Mi , Tsao Philip S. , Rader Daniel J. , Ritchie Marylyn D. , Damrauer Scott M. , Voight Benjamin F. TITLE=Multi-Trait Genome-Wide Association Study of Atherosclerosis Detects Novel Pleiotropic Loci JOURNAL=Frontiers in Genetics VOLUME=12 YEAR=2022 URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.787545 DOI=10.3389/fgene.2021.787545 ISSN=1664-8021 ABSTRACT=

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. To identify novel pleiotropic loci associated with atherosclerosis, we performed a joint analysis of their shared genetic architecture, along with that of common risk factors. Using summary statistics from genome-wide association studies of nine known atherosclerotic (CAD, PAD) and atherosclerosis risk factors (body mass index, smoking initiation, type 2 diabetes, low density lipoprotein, high density lipoprotein, total cholesterol, and triglycerides), we perform 15 separate multi-trait genetic association scans which resulted in 25 novel pleiotropic loci not yet reported as genome-wide significant for their respective traits. Colocalization with single-tissue eQTLs identified candidate causal genes at 14 of the detected signals. Notably, the signal between PAD and LDL-C at the PCSK6 locus affects PCSK6 splicing in human liver tissue and induced pluripotent derived hepatocyte-like cells. These results show that joint analysis of related atherosclerotic disease traits and their risk factors allowed identification of unified biology that may offer the opportunity for therapeutic manipulation. The signal at PCSK6 represent possible shared causal biology where existing inhibitors may be able to be leveraged for novel therapies.