One score to rule them all: regularized ensemble polygenic risk prediction with GWAS summary statistics

Ensemble learning has been increasingly popular for boosting the predictive power of polygenic risk scores (PRS), with almost every recent multi-ancestry PRS approach employing ensemble learning as a final step. Existing ensemble approaches rely on individual-level data for model training, which severely limits their real-world applications, especially in non-European populations without sufficient genomic samples. Here, we introduce a statistical framework to construct regularized ensemble PRS, which allows us to combine a large number of candidate PRS models using only summary statistics from genome-wide association studies. We demonstrate its robust and substantial improvement over many existing PRS models in both within- and cross-ancestry applications. We believe this is truly "one score to rule them all" due to its capability to continuously combine newly developed PRS models with existing models to improve prediction performance, which makes it a universal approach that should always be employed in future PRS applications.