Shared components of heritability across genetically correlated traits.

Most disease-associated genetic variants are pleiotropic, affecting multiple genetically correlated traits. Their pleiotropic associations can be mechanistically informative: if many variants have similar patterns of association, they may act via similar pleiotropic mechanisms, forming a shared component of heritability. We developed pleiotropic decomposition regression (PDR) to identify shared components and their underlying genetic variants. We validated PDR on simulated data and identified limitations of existing methods in recovering the true components. We applied PDR to three clusters of five to six traits genetically correlated with coronary artery disease (CAD), asthma, and type II diabetes (T2D), producing biologically interpretable components. For CAD, PDR identified components related to BMI, hypertension, and cholesterol, and it clarified the relationship among these highly correlated risk factors. We assigned variants to components, calculated their posterior-mean effect sizes, and performed out-of-sample validation. Our posterior-mean effect sizes pool statistical power across traits and substantially boost the correlation (r2) between true and estimated effect sizes (compared with the original summary statistics) by 94% and 70% for asthma and T2D out of sample, respectively, and by a predicted 300% for CAD.