Risk factors affecting polygenic score performance across diverse cohorts

Apart from ancestry, personal or environmental covariates may contribute to differences in polygenic score (PGS) performance. We analyzed effects of covariate stratification and interaction on body mass index (BMI) PGS (PGS_BMI) across four cohorts of European (N=491,111) and African (N=21,612) ancestry. Stratifying on binary covariates and quintiles for continuous covariates, 18/62 covariates had significant and replicable R²differences among strata. Covariates with the largest differences included age, sex, blood lipids, physical activity, and alcohol consumption, with R²being nearly double between best and worst performing quintiles for certain covariates. 28 covariates had significant PGS_BMI-covariate interaction effects, modifying PGS_BMIeffects by nearly 20% per standard deviation change. We observed overlap between covariates that had significant R²differences among strata and interaction effects – across all covariates, their main effects on BMI were correlated with their maximum R²differences and interaction effects (0.56 and 0.58, respectively), suggesting high-PGS_BMIindividuals have highest R²and increase in PGS effect. Using quantile regression, we show the effect of PGS_BMIincreases as BMI itself increases, and that these differences in effects are directly related to differences in R²when stratifying by different covariates. Given significant and replicable evidence for context-specific PGS_BMIperformance and effects, we investigated ways to increase model performance taking into account non-linear effects. Machine learning models (neural networks) increased relative model R²(mean 23%) across datasets. Finally, creating PGS_BMIdirectly from GxAge GWAS effects increased relative R²by 7.8%. These results demonstrate that certain covariates, especially those most associated with BMI, significantly affect both PGS_BMIperformance and effects across diverse cohorts and ancestries, and we provide avenues to improve model performance that consider these effects.