Broad Clinical Manifestations of Polygenic Risk for Coronary Artery Disease in the Women's Health Initiative

Overview

Journal Commun Med (Lond)

Publisher Nature Portfolio

Specialty General Medicine

Date 2022 Aug 29

PMID 36034645

Authors

Shoa L Clarke

Matthew Parham

Joanna Lankester

Aladdin H Shadyab

Simin Liu

Charles Kooperberg

JoAnn E Manson

Catherine Tcheandjieu

Themistocles L Assimes

Affiliations

Soon will be listed here.

Abstract

Background: The genetic basis for coronary artery disease (CAD) risk is highly complex. Genome-wide polygenic risk scores (PRS) can help to quantify that risk, but the broader impacts of polygenic risk for CAD are not well characterized.

Methods: We measured polygenic risk for CAD using the meta genomic risk score, a previously validated genome-wide PRS, in a subset of genotyped participants from the Women's Health Initiative and applied a phenome-wide association study framework to assess associations between the PRS and a broad range of blood biomarkers, clinical measurements, and health outcomes.

Results: Polygenic risk for CAD is associated with a variety of biomarkers, clinical measurements, behaviors, and diagnoses related to traditional risk factors, as well as risk-enhancing factors. Analysis of adjudicated outcomes shows a graded association between atherosclerosis related outcomes, with the highest odds ratios being observed for the most severe manifestations of CAD. We find associations between increased polygenic risk for CAD and decreased risk for incident breast and lung cancer, with replication of the breast cancer finding in an external cohort. Genetic correlation and two-sample Mendelian randomization suggest that breast cancer association is likely due to horizontal pleiotropy, while the association with lung cancer may be causal.

Conclusion: Polygenic risk for CAD has broad clinical manifestations, reflected in biomarkers, clinical measurements, behaviors, and diagnoses. Some of these associations may represent direct pathways between genetic risk and CAD while others may reflect pleiotropic effects independent of CAD risk.

Citing Articles

Inference of Causal Relationships Between Genetic Risk Factors for Cardiometabolic Phenotypes and Female-Specific Health Conditions.

Xiao B, Velez Edwards D, Lucas A, Drivas T, Gray K, Keating B J Am Heart Assoc. 2023; 12(5):e026561.

PMID: 36846987 PMC: 10111435. DOI: 10.1161/JAHA.121.026561.

Large-scale genome-wide association study of coronary artery disease in genetically diverse populations.

Tcheandjieu C, Zhu X, Hilliard A, Clarke S, Napolioni V, Ma S Nat Med. 2022; 28(8):1679-1692.

PMID: 35915156 PMC: 9419655. DOI: 10.1038/s41591-022-01891-3.

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