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Author Notes:

Benjamin F. Voight, bvoight@penmedicine.upenn.edu

TB and WB ran experiments, interpreted results, and wrote the manuscript BC, KG, DZ, JP ran experiments for follow up analyses on loci BC, ML, NT wrote code for performing analyses DK, JL, TA, JG, PW, KC, MV, CO, K-MC, PT collected data to make these experiments possible DR and MR helped interpret results, provided data for follow up experiments, and helped write the manuscript SD and BV oversaw the project, helped interpret results, and helped write the manuscript.

SD receives research support to his institution from RenalytixAI and personal consulting frees from Calico Labs, both outside the current work. CO is employed by Novartis Institutes of Biomedical Research. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Subjects:

Research Funding:

This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by awardno. MVP000. This publication does not represent the views of the Department of Veteran Affairs or the United States Government. This research was also supported by funding from: the Department of Veterans Affairs awards nos. I01-BX03340 (KC and PW), I01-BX003362 (PT and KC), and IK2-CX001780 (SD), the National Institutes of Health (DK101478 and DK126194 to BV), the American Heart Association (20PRE35120109 to WB).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Genetics & Heredity
  • peripheral artery disease
  • atherosclerosis
  • multi-trait analyses
  • GWAS-genome-wide association study
  • pleiotropy
  • GENETIC-VARIATION
  • DISEASE
  • IDENTIFICATION
  • VARIANTS
  • PATHWAYS
  • PROTEASE
  • INDEX
  • PCSK6

Multi-Trait Genome-Wide Association Study of Atherosclerosis Detects Novel Pleiotropic Loci

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Journal Title:

FRONTIERS IN GENETICS

Volume:

Volume 12

Publisher:

, Pages 787545-787545

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2022 Bellomo, Bone, Chen, Gawronski, Zhang, Park, Levin, Tsao, Klarin, Lynch, Assimes, Gaziano, Wilson, Cho, Vujkovic, the VA Million Veteran Program, O’Donnell, Chang, Tsao, Rader, Ritchie, Damrauer and Voight.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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