Abstract
Polygenic risk scores (PRSs) are an emerging tool to predict the clinical phenotypes and outcomes of individuals. We propose PRSmix, a framework that leverages the PRS corpus of a target trait to improve prediction accuracy, and PRSmix+, which incorporates genetically correlated traits to better capture the human genetic architecture for 47 and 32 diseases/traits in European and South Asian ancestries, respectively. PRSmix demonstrated a mean prediction accuracy improvement of 1.20-fold (95% confidence interval [CI], [1.10; 1.3]; p = 9.17 × 10(-5)) and 1.19-fold (95% CI, [1.11; 1.27]; p = 1.92 × 10(-6)), and PRSmix+ improved the prediction accuracy by 1.72-fold (95% CI, [1.40; 2.04]; p = 7.58 × 10(-6)) and 1.42-fold (95% CI, [1.25; 1.59]; p = 8.01 × 10(-7)) in European and South Asian ancestries, respectively. Compared to the previously cross-trait-combination methods with scores from pre-defined correlated traits, we demonstrated that our method improved prediction accuracy for coronary artery disease up to 3.27-fold (95% CI, [2.1; 4.44]; p value after false discovery rate (FDR) correction = 2.6 × 10(-4)). Our method provides a comprehensive framework to benchmark and leverage the combined power of PRS for maximal performance in a desired target population.