Incorporating multiple functional annotations to improve polygenic risk prediction accuracy.

We present OmniPRS, a scalable biobank-scale framework that improves genetic risk prediction for complex traits by integrating genome-wide association study (GWAS) summary statistics and functional annotations. It employs a mixed model incorporating tissue-specific genetic variance components from annotations to re-estimate single-nucleotide polymorphism (SNP) effects and constructs tissue-specific polygenic risk scores (PRSs) and aggregates them into the final OmniPRS. Our experiments, encompassing 135 simulation scenarios and 11 representative traits, demonstrate that OmniPRS is flexible and robust, delivering efficient and accurate predictions comparable to ten leading PRS methods. For quantitative (binary) traits, OmniPRS achieved an average improvement of 52.31% (19.83%) versus the clumping and thresholding (C+T) method, 3.92% (1.31%) versus the annotation-integrated PRSs (LDpred-funct), and 8.44% (2.27%) versus the Bayesian-based PRSs (PRScs). Notably, it achieved 35× faster computation than the PRScs. This rapid, precise framework enables efficient polygenic risk scoring with multi-annotation integration for large-scale genomic studies.