Abstract 4369085: Impact of Family History and Polygenic Risk Scores on Cardiometabolic Disease Risk

Introduction: Cardiometabolic diseases (CMD) remain a leading contributor to global morbidity and mortality. While both family history (FH) and polygenic risk scores (PRS) are established predictors of CMD, their combined and comparative utility remains underexplored. This study evaluated the independent and joint effects of FH and PRS on CMD risk in the All of Us Research Program, a large, ancestrally diverse cohort. Research Question: To what extent do family history and polygenic risk scores independently and jointly predict cardiometabolic disease risk, and is there evidence of an interaction between these factors? Methods: We analyzed cross-sectional data from 103,566 adults with genotype and self-reported FH information. CMD phenotypes including type 2 diabetes (T2D), obesity, essential hypertension, and coronary artery disease (CAD) were identified via electronic health records. Multi-ancestry PRS were derived using validated multi-ancestry PRS weights from the PGS Catalog. Logistic regression assessed associations of FH and PRS with CMDs independently and jointly adjusting for relevant covariates. We further tested multiplicative interaction and performed mediation analysis to assess the proportion of FH effects explained by PRS. Results: FH was significantly associated with increased risk for all CMDs, with the strongest association observed for obesity (OR: 2.09; 95% CI: 2.01 - 2.16). PRS was independently predictive, with the largest effect seen for T2D (OR: 2.25; 95% CI: 2.18 - 2.33). Significant FH × PRS interactions were identified for obesity (p < 0.001) and CAD (p = 0.03).Individuals with both a positive FH and high PRS had substantially elevated odds of disease compared to those with no FH and intermediate PRS for T2D (OR: 3.82; 95% CI: 3.55 - 4.13), obesity (OR: 3.19; 95% CI: 3.00 - 3.39), essential hypertension (OR: 2.26; 95% CI: 2.16 - 2.37), and CAD (OR: 3.26; 95% CI: 3.03 - 3.50). Mediation analysis indicated that PRS explained 13%, 15%, 16%, and 20% of the FH effect on CAD, obesity, T2D, and essential hypertension respectively. Conclusions: FH and PRS provide complementary, additive information for CMD risk prediction. FH reflects both inherited genetic predisposition and shared environmental exposures, while PRS provides a quantifiable measure of genetic liability. Integrating both measures may improve risk stratification and inform precision prevention strategies.