PT  - JOURNAL ARTICLE
AU  - Zhao, Zijie
AU  - Gruenloh, Tim
AU  - Wu, Yixuan
AU  - Sun, Zhongxuan
AU  - Miao, Jiacheng
AU  - Wu, Yuchang
AU  - Song, Jie
AU  - Lu, Qiongshi
TI  - Optimizing and benchmarking polygenic risk scores with GWAS summary statistics
AID  - 10.1101/2022.10.26.513833
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.10.26.513833
4099  - http://biorxiv.org/content/early/2022/11/07/2022.10.26.513833.short
4100  - http://biorxiv.org/content/early/2022/11/07/2022.10.26.513833.full
AB  - We introduce an innovative statistical framework to optimize and benchmark polygenic risk score (PRS) models using summary statistics of genome-wide association studies. This framework builds upon our previous work and can fine-tune virtually all existing PRS models while accounting for linkage disequilibrium. In addition, we provide an ensemble learning strategy named PUMA-CUBS to combine multiple PRS models into an ensemble score without requiring external data for model fitting. Through extensive simulations and analysis of many complex traits in the UK Biobank, we demonstrate that this approach closely approximates gold-standard analytical strategies based on external validation, and substantially outperforms state-of-the-art PRS methods. We argue that PUMA-CUBS is a powerful and general modeling technique that can continue to combine the best-performing PRS methods out there through ensemble learning and could become an integral component for all future PRS applications.Competing Interest StatementThe authors have declared no competing interest.