Studying rare variant polygenic risk scores using whole exome sequencing and imputed genotype data.

ABSTRACT: Rare variant polygenic scores (rvPRS) are developed to improve phenotype prediction, yet a standardized construction protocol remains unavailable. We aim 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 are constructed for 13 binary and 5 quantitative traits using gene-burden and single-SNP associations and are assessed via R², perSD OR/Beta, NRI, and IDI. Single-SNP-based rvPRS outperform gene-burden models, and IMP-derived rvPRS generally surpass WES-derived models. For 6 of 12 validated traits, combined tPRS (cvPRS + rvPRS) improves prediction over cvPRS alone. IMP data also show a stronge

SUBMITTER: Kang JO 

PROVIDER: S-EPMC12749733 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature