Rare variant polygenic risk scores using WES and IMP

<br>Rare variant polygenic scores (rvPRS) are being developed to improve phenotype prediction, yet a standardized construction protocol remains unavailable. We sought to establish an optimal rvPRS protocol using whole exome sequencing (WES) and imputed genotype (IMP) data from 502,369 UK Biobank participants and to evaluate its predictive performance compared to common variant PRS (cvPRS). rvPRS models were constructed for 13 binary and 5 quantitative traits using gene-burden and single-SNP associations and assessed via <i>R</i>², perSD OR/Beta, NRI, and IDI. Single-SNP-based rvPRS outperformed gene-burden models, and IMP-derived rvPRS generally surpassed WES-derived models. For 6 of 12 validated traits, combined tPRS (cvPRS + rvPRS) improved prediction over cvPRS alone. IMP data also showed a stronger correlation between heritability and rvPRS association strength. This study provides a practical rvPRS protocol applicable across traits and underscores the potential of rare variants to enhance phenotype prediction.