Functional gene embeddings improve rare variant polygenic risk scores
Rare variant association testing is a powerful strategy for identifying effector genes underlying common traits. However, its effectiveness is limited by the scarcity of high-impact rare allele carriers, posing challenges for sensitivity and robustness. Here, we introduce FuncRVP, a rare variant association framework addressing this issue by leveraging functional information across genes. FuncRVP models the effects of rare variants as a weighted sum of gene impairment scores, with weights regularized through a prior based on functional gene embeddings. Modeling 41 quantitative traits from unrelated UK Biobank participants showed that FuncRVP consistently outperformed linear regressions on significantly associated genes and did so more effectively for traits with higher burden heritability. The framework demonstrated versatility, yielding consistent improvements across diverse gene embeddings. Moreover, FuncRVP generated more robust gene effect estimates and yielded more gene discoveries, especially among genetically constrained genes. These findings demonstrate the value of integrating functional information in rare variant association studies and showcase FuncRVP as a promising tool for enhancing phenotype prediction and gene discovery.