Leveraging polygenic enrichments of gene features to predict genes underlying complex traits and diseases

Polygenic Priority Score (PoPS) prioritizes candidate effector genes at complex trait loci by integrating genome-wide association summary statistics with other data types. Combining PoPS with methods that leverage local genetic signals further improves the performance. Genome-wide association studies (GWASs) are a valuable tool for understanding the biology of complex human traits and diseases, but associated variants rarely point directly to causal genes. In the present study, we introduce a new method, polygenic priority score (PoPS), that learns trait-relevant gene features, such as cell-type-specific expression, to prioritize genes at GWAS loci. Using a large evaluation set of genes with fine-mapped coding variants, we show that PoPS and the closest gene individually outperform other gene prioritization methods, but observe the best overall performance by combining PoPS with orthogonal methods. Using this combined approach, we prioritize 10,642 unique gene-trait pairs across 113 complex traits and diseases with high precision, finding not only well-established gene-trait relationships but nominating new genes at unresolved loci, such as LGR4 for estimated glomerular filtration rate and CCR7 for deep vein thrombosis. Overall, we demonstrate that PoPS provides a powerful addition to the gene prioritization toolbox.

Automated summary

Polygenic Priority Score (PoPS) integrates genome-wide association summary statistics with other data types to prioritize candidate effector genes at complex trait loci. Combining PoPS with methods that leverage local genetic signals improves performance. In this study, PoPS is introduced as a new method to prioritize genes at GWAS loci by learning trait-relevant gene features. By combining PoPS with orthogonal methods, 10,642 unique gene-trait pairs across 113 complex traits and diseases are prioritized with high precision, including both well-established gene-trait relationships and new genes at unresolved loci.