Pleiotropic shared heritability quantifies the shared genetic variance of common diseases

Abstract The overall contribution of pleiotropy to disease architectures is unknown, as most studies estimate genetic correlations with each auxiliary disease in turn. Here we propose a method—pleiotropic shared heritability with bias correction (PHBC)—to estimate the liability-scale genetic variance of a target disease that is shared with a specific set of auxiliary diseases ( $${{h}^{2}}_{\mathrm{pleio}}$$ h 2 pleio ). PHBC estimates $${{h}^{2}}_{\mathrm{pleio}}$$ h 2 pleio from a genetic correlation matrix using a Monte Carlo bias correction procedure to account for sampling noise. The average ratio of $${{h}^{2}}_{\mathrm{pleio}}$$ h 2 pleio to total single-nucleotide polymorphism heritability ( $${{h}^{2}}_{\mathrm{pleio}}/{h}^{2}$$ h 2 pleio / h 2 ) across 15 UK Biobank diseases (spanning seven disease categories) was 27 ± 3%, increasing to 48 ± 5% when expanding to 62 auxiliary diseases/traits. $${{h}^{2}}_{\mathrm{pleio}}/{h}^{2}$$ h 2 pleio / h 2 was broadly distributed across disease categories, decreasing only modestly when removing the most informative auxiliary disease categories. The average $${{h}^{2}}_{\mathrm{pleio}}/{h}^{2}$$ h 2 pleio / h 2 was 1.51 ± 0.16-times larger than the proportion of total phenotypic variance explained by auxiliary diseases, implying higher pleiotropy for genetic effects. In summary, roughly half of common disease heritability is pleiotropic with a broad range of diseases.