Shi J, Park JH, Duan J, Berndt ST, Moy W, Yu K, Song L, Wheeler W, Hua X, Silverman D, Garcia-Closas M, Hsiung CA, Figueroa JD, Cortessis VK, Malats N, Karagas MR, Vineis P, Chang IS, Lin D, Zhou B, Seow A, Matsuo K, Hong YC, Caporaso NE, Wolpin B, Jacobs E, Petersen GM, Klein AP, Li D, Risch H, Sanders AR, Hsu L, Schoen RE, Brenner H, MGS (Molecular Genetics of Schizophrenia) GWAS Consortium, GECCO (The Genetics and Epidemiology of Colorectal Cancer Consortium), GAME-ON/TRICL (Transdisciplinary Research in Cancer of the Lung) GWAS Consortium, PRACTICAL (PRostate cancer AssoCiation group To Investigate Cancer Associated aLterations) Consortium, PanScan Consortium, GAME-ON/ELLIPSE Consortium, Stolzenberg-Solomon R, Gejman P, Lan Q, Rothman N, Amundadottir LT, Landi MT, Levinson DF, Chanock SJ, Chatterjee N

Recent heritability analyses have indicated that genome-wide association studies (GWAS) have the potential to improve genetic risk prediction for complex diseases based on polygenic risk score (PRS), a simple modelling technique that can be implemented using summary-level data from the discovery samples. We herein propose modifications to improve the performance of PRS. We introduce threshold-dependent winner's-curse adjustments for marginal association coefficients that are used to weight the single-nucleotide polymorphisms (SNPs) in PRS. Further, as a way to incorporate external functional/annotation knowledge that could identify subsets of SNPs highly enriched for associations, we propose variable thresholds for SNPs selection. We applied our methods to GWAS summary-level data of 14 complex diseases. Across all diseases, a simple winner's curse correction uniformly led to enhancement of performance of the models, whereas incorporation of functional SNPs was beneficial only for selected diseases. Compared to the standard PRS algorithm, the proposed methods in combination led to notable gain in efficiency (25-50% increase in the prediction R2) for 5 of 14 diseases. As an example, for GWAS of type 2 diabetes, winner's curse correction improved prediction R2 from 2.29% based on the standard PRS to 3.10% (P = 0.0017) and incorporating functional annotation data further improved R2 to 3.53% (P = 2×10-5). Our simulation studies illustrate why differential treatment of certain categories of functional SNPs, even when shown to be highly enriched for GWAS-heritability, does not lead to proportionate improvement in genetic risk-prediction because of non-uniform linkage disequilibrium structure.