Quantifying annotation-stratified pleiotropy and co-polygenicity between complex traits

Abstract

Understanding shared genetic architecture is essential to interpreting disease comorbidities and trait correlations. We introduce SBayesAPP, a Bayesian model that integrates GWAS summary statistics with functional annotations to jointly estimate annotation-stratified SNP effect-size correlation and pleiotropic variant proportion (co-polygenicity) between traits, dissecting genetic correlation and coheritability enrichment across annotations. Simulations and real data analyses show improved accuracy and interpretability over existing methods. In type 2 diabetes analyses with 15 traits, SBayesAPP reveals clear tissue- and cell-type-specific enrichment and distinguishes mechanisms driven by few large-effect variants versus many modest-effect variants. The analysis of smoking and lung cancer prioritizes lung and immune cells, and identifies cell-type-specific genetic correlations driven by either pleiotropic or lung-cancer-specific variants, consistent with a causal relationship model. For schizophrenia and educational attainment, despite near-zero genome-wide genetic correlation, cell-type-specific correlations range from -0.20 to 0.21, with strong (co)heritability enrichment and high co-polygenicity found in dopaminergic neurons and oligodendrocytes. These results highlight the ability of SBayesAPP to resolve annotation-specific genetic sharing and uncover biological mechanisms across complex traits.