Pleiotropic shared heritability quantifies the shared genetic variance of common diseases

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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.

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