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Updated: Oct 3, 2025

Large-Scale Multi-Omics Genome-Wide Association Studies Mo-GWAS: Guidelines for Sample Preparation and Normalization
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Large-Scale Multi-Omics Genome-Wide Association Studies Mo-GWAS: Guidelines for Sample Preparation and Normalization

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

Tiffany R Bellomo1, William P Bone2, Brian Y Chen3

  • 1Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.

Frontiers in Genetics
|February 21, 2022
PubMed

Insights

This study identified 25 new genetic loci linked to coronary artery disease (CAD) and peripheral artery disease (PAD). A key finding at the PCSK6 locus suggests a shared biological pathway for potential new therapies.

Area of Science:

  • Genetics
  • Cardiovascular Disease
  • Metabolic Disease

Background:

  • Coronary artery disease (CAD) and peripheral artery disease (PAD) are related atherosclerotic vascular diseases with shared risk factors and pathobiology.
  • Identifying shared genetic underpinnings is crucial for understanding atherosclerosis and developing unified therapeutic strategies.

Purpose of the Study:

  • To discover novel pleiotropic genetic loci associated with atherosclerosis by jointly analyzing CAD, PAD, and their common risk factors.
  • To identify shared genetic architecture and potential causal genes underlying these related cardiovascular conditions.

Main Methods:

  • Performed 15 multi-trait genetic association scans using genome-wide association study summary statistics for CAD, PAD, and nine risk factors (BMI, smoking, diabetes, lipids, triglycerides).
  • Utilized colocalization analysis with single-tissue expression quantitative trait loci (eQTLs) to identify candidate causal genes at novel loci.

Main Results:

  • Identified 25 novel pleiotropic loci associated with atherosclerosis and its risk factors, not previously reported at genome-wide significance.
  • Candidate causal genes were identified at 14 of these loci through eQTL colocalization.
  • A significant signal at the PCSK6 locus was found to affect PCSK6 splicing in liver tissue, linking PAD and LDL-C.

Conclusions:

  • Joint analysis of related atherosclerotic diseases and risk factors effectively revealed unified biological pathways.
  • The identified PCSK6 signal suggests a shared causal mechanism that could be targeted by existing inhibitors for novel therapeutic interventions.

Keywords:
GWAS—genome-wide association studyatherosclerosismulti-trait analysesperipheral artery diseasepleiotropy

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