Biomaterial Database

MUSSEL: Enhanced Bayesian Polygenic Risk Prediction Leveraging Information across Multiple Ancestry Groups. 2023

Jin Jin, and Jianan Zhan, and Jingning Zhang, and Ruzhang Zhao, and Jared O'Connell, and Yunxuan Jiang, and , and Steven Buyske, and Christopher Gignoux, and Christopher Haiman, and Eimear E Kenny, and Charles Kooperberg, and Kari North, and Bertram L Koelsch, and Genevieve Wojcik, and Haoyu Zhang, and Nilanjan Chatterjee

Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Polygenic risk scores (PRS) are now showing promising predictive performance on a wide variety of complex traits and diseases, but there exists a substantial performance gap across different populations. We propose MUSSEL, a method for ancestry-specific polygenic prediction that borrows information in the summary statistics from genome-wide association studies (GWAS) across multiple ancestry groups. MUSSEL conducts Bayesian hierarchical modeling under a MUltivariate Spike-and-Slab model for effect-size distribution and incorporates an Ensemble Learning step using super learner to combine information across different tuning parameter settings and ancestry groups. In our simulation studies and data analyses of 16 traits across four distinct studies, totaling 5.7 million participants with a substantial ancestral diversity, MUSSEL shows promising performance compared to alternatives. The method, for example, has an average gain in prediction R2 across 11 continuous traits of 40.2% and 49.3% compared to PRS-CSx and CT-SLEB, respectively, in the African Ancestry population. The best-performing method, however, varies by GWAS sample size, target ancestry, underlying trait architecture, and the choice of reference samples for LD estimation, and thus ultimately, a combination of methods may be needed to generate the most robust PRS across diverse populations.