Integrating multiple traits for improving polygenic risk prediction in disease and pharmacogenomics GWAS

Polygenic risk score (PRS) has been recently developed for predicting complex traits and drug responses. It remains unknown whether multi-trait PRS (mtPRS) methods, by integrating information from multiple genetically correlated traits, can improve prediction accuracy and power for PRS analysis compared with single-trait PRS (stPRS) methods. In this paper, we first review commonly used mtPRS methods and find that they do not directly model the underlying genetic correlations among traits, which has been shown to be useful in guiding multi-trait association analysis in the literature. To overcome this limitation, we propose a mtPRS-PCA method to combine PRSs from multiple traits with weights obtained from performing principal component analysis (PCA) on the genetic correlation matrix. To accommodate various genetic architectures covering different effect directions, signal sparseness and across-trait correlation structures, we further propose an omnibus mtPRS method (mtPRS-O) by combining P values from mtPRS-PCA, mtPRS-ML (mtPRS based on machine learning) and stPRSs using Cauchy Combination Test. Our extensive simulation studies show that mtPRS-PCA outperforms other mtPRS methods in both disease and pharmacogenomics (PGx) genome-wide association studies (GWAS) contexts when traits are similarly correlated, with dense signal effects and in similar effect directions, and mtPRS-O is consistently superior to most other methods due to its robustness under various genetic architectures. We further apply mtPRS-PCA, mtPRS-O and other methods to PGx GWAS data from a randomized clinical trial in the cardiovascular domain and demonstrate performance improvement of mtPRS-PCA in both prediction accuracy and patient stratification as well as the robustness of mtPRS-O in PRS association test.