Implementing a Multi-Ancestry Polygenic Risk Score for Coronary Heart Disease in a Diverse Cohort

We describe a prospective cohort study (NCT05277116) conducted in phase IV of the electronic MEdical Records and GEnomics (eMERGE) Network to implement a multi-ancestry polygenic risk score for coronary heart disease (PRS_CHD: PGS004696) and assess outcomes after return of results (RoR).

PRS_CHD was considered alongside family history (FamHx_CHD), monogenic risk from familial hypercholesterolemia (FH), and clinical risk factors, to return CHD risk as part of a Genome Informed Risk Assessment (GIRA) report. Participants with high PRS_CHD (top 5^th percentile) or FH received their results from study personnel, while participants with FamHx_CHD were informed by mail/email. Results were placed in the electronic health record and communicated to the primary care provider. The primary outcome of initiation/intensification of lipid lowering therapy within 12 months after RoR is compared between participants with PRS_CHD ≥95^th percentile and those with PRS_CHD 90^th-94^th percentile, using a regression discontinuity design. Secondary outcomes include ordering of screening tests, a new CHD diagnosis, and lifestyle changes.

By April 2025, 20,421 adults were enrolled: mean age 50±15 years (range 18-75 years), 68% female, 50% belonging to health disparity groups, and 40% non-White by self-report. Prevalence of CHD, FamHx_CHD, high PRS_CHD and FH was 4.0%, 10.2%, 4.3% and 0.7%, respectively; 14.3% had at least one of the three CHD genetic risk factors and CHD risk estimates were highest in those who self-reported as Black.

The prevalence of increased genetic risk for CHD was high and at least one of the three genetic risk factors for CHD was present in 14.2% of the cohort. Analyses are underway to assess outcomes after PRS_CHD implementation in the context of FamHx_CHD, FH, and clinical risk, across the age spectrum in a diverse cohort.