Evaluating the impact of family history and polygenic risk scores on cardiometabolic disease risk

Cardiometabolic diseases (CMD) are a leading cause of morbidity and mortality. While both family history (FH) and polygenic risk scores (PRS) are predictive of CMD risk, few studies have systematically evaluated their independent and joint effects. This study aimed to quantify the individual contributions of FH and PRS, as well as their combined impact on CMD risk.

We conducted an analysis of more than 120,000 adults from the All of Us Research Program with available genotypic, phenotypic, and FH data. CMDs including type 2 diabetes (T2D), obesity, hypertension (HTN), and coronary artery disease (CAD) were ascertained from electronic health records. FH was derived from self-reported survey responses, and family history scores (FHS) were constructed by weighting the number and degree of affected relatives. PRSs were computed using validated multi-ancestry PRS weights from the PGS catalog. Cox proportional hazard regression was used to assess associations of FH, FHS, and PRS independently and jointly with CMD in the overall cohort and stratified by genetic ancestry. We also tested for FHS × PRS interactions and conducted mediation analysis.

Positive FH was significantly associated with increased risk of all CMDs, with the strongest effect observed for obesity (HR 2.07, 95% CI: 2.02-2.12). FHS showed the strongest association with T2D (HR 1.34, 95% CI: 1.32-1.37). Higher PRS values were also associated with elevated disease risk, most strongly for T2D (HR 2.13, 95% CI: 2.07 -2.18). FHS and PRS associations were attenuated in the African ancestry population. A statistically significant interaction between FHS and PRS was observed for obesity (p < 0.001). Individuals with a positive FH and high PRS have greater than 2.5-fold risk of developing CMDs compared to those with negative FH and an intermediate PRS. Mediation analysis indicated that PRS accounted for between 13 and 16% of the total effect of FHS across all traits.

Both FH and PRS are associated with CMD risk and provide complementary but distinct insights into disease risk. PRS adds predictive value beyond FH and partially mediates its effect. Integration of both measures may enhance risk stratification and guide precision prevention strategies.