| Title: | Pleiotropic shared heritability quantifies the shared genetic variance of common diseases |
| Journal: | Nature Genetics |
| Published: | 9 Jun 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42265310/ |
| DOI: | https://doi.org/10.1038/s41588-026-02607-w |
Publication 20744
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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 (h2pleio$${{h}^{2}}_{\mathrm{pleio}}$$). PHBC estimates h2pleio$${{h}^{2}}_{\mathrm{pleio}}$$ from a genetic correlation matrix using a Monte Carlo bias correction procedure to account for sampling noise. The average ratio of h2pleio$${{h}^{2}}_{\mathrm{pleio}}$$ to total single-nucleotide polymorphism heritability (h2pleio/h2$${{h}^{2}}_{\mathrm{pleio}}/{h}^{2}$$) across 15 UK Biobank diseases (spanning seven disease categories) was 27 ± 3%, increasing to 48 ± 5% when expanding to 62 auxiliary diseases/traits. h2pleio/h2$${{h}^{2}}_{\mathrm{pleio}}/{h}^{2}$$ was broadly distributed across disease categories, decreasing only modestly when removing the most informative auxiliary disease categories. The average h2pleio/h2$${{h}^{2}}_{\mathrm{pleio}}/{h}^{2}$$ 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.</p>
11 Keywords
- Disease
- Genetic Pleiotropy
- Genetic Predisposition to Disease
- Genetic Variation
- Genome-Wide Association Study
- Humans
- Models, Genetic
- Monte Carlo Method
- Phenotype
- Polymorphism, Single Nucleotide
- UK Biobank
10 Authors
- Yujie Zhao
- Benjamin Strober
- Kangcheng Hou
- Gaspard Kerner
- John Danesh
- Steven Gazal
- Wei Cheng
- Michael Inouye
- Alkes L. Price
- Xilin Jiang
1 Application
| Application ID | Title |
|---|---|
| 19542 | Identifying multi-level biomarkers and disease mechanisms for major mental disorders |
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