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

Abstract

BackgroundThe 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. MethodsWe measured polygenic risk for CAD using the metaGRS, a previously validated genome-wide PRS, in a subset of genotyped participants from the Womens Health Initiative (WHI) and applied a phenome-wide association study framework to assess associations between the PRS and broad range of blood biomarkers, clinical measurements, and outcomes. ResultsPolygenic risk for CAD was 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 showed a graded association between atherosclerosis related outcomes, with the highest odds ratios being observed for the most severe manifestations of CAD. We identified novel 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. ConclusionPolygenic 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.