PGS-server: accuracy, robustness and transferability of polygenic score methods for biobank scale studies.

Polygenic scores (PGS) are important tools for carrying out genetic prediction of common diseases and disease related complex traits, facilitating the development of precision medicine. Unfortunately, despite the critical importance of PGS and the vast number of PGS methods recently developed, few comprehensive comparison studies have been performed to evaluate the effectiveness of PGS methods. To fill this critical knowledge gap, we performed a comprehensive comparison study on 12 different PGS methods through internal evaluations on 25 quantitative and 25 binary traits within the UK Biobank with sample sizes ranging from 147 408 to 336 573, and through external evaluations via 25 cross-study and 112 cross-ancestry analyses on summary statistics from multiple genome-wide association studies with sample sizes ranging from 1415 to 329 345. We evaluate the prediction accuracy, computational scalability, as well as robustness and transferability of different PGS methods across datasets and/or genetic ancestries, providing important guidelines for practitioners in choosing PGS methods. Besides method comparison, we present a simple aggregation strategy that combines multiple PGS from different methods to take advantage of their distinct benefits to achieve stable and superior prediction performance. To facilitate future applications of PGS, we also develop a PGS webserver (http://www.pgs-server.com/) that allows users to upload summary statistics and choose different PGS methods to fit the data directly. We hope that our results, method and webserver will facilitate the routine application of PGS across different research areas.