Abstract
Epidemiological literature describes widespread psychiatric–physical comorbidity. However, the extent to which observed bivariate risk is transdiagnostic remains uncertain. We apply Genomic SEM and introduce Genomic E-SEM, an exploratory factor-analytic extension of Genomic SEM, here applied to 73 physical outcomes (~1.9 million cases) across eight medical domains. We then modeled latent physical illness factors alongside previously identified psychiatric factors. Thought/psychotic and compulsive factors exhibited few associations with physical illness factors. Conversely, internalizing, neurodevelopmental, and substance-use factors showed substantial genome-wide genetic correlations with all physical illness systems. Multivariate GWAS of a transdiagnostic physical illness factor, defined by 21 physical disorders, identified 27 genomic risk loci and exhibited substantial predictive validity in subsequent PheWAS. This transdiagnostic factor again exhibited substantial genome-wide genetic correlations with internalizing, neurodevelopmental, and substance-use factors. Our results reveal pervasive risk sharing between specific groups of psychiatric and physical conditions and suggest the need for additional nosological frameworks.
Data availability
The data sources for each of the GWAS summary statistics are available in Supplementary Data 7 for physical phenotypes and Supplementary Data 8 for psychiatric phenotypes. No new data were collected for this project, and all data utilized in this study were from publicly available sources. GWAS summary statistics for the physical illness factor are available at https://figshare.com/projects/Shared_Genetic_Liability_across_Systems_of_Psychiatric_and_Physical_Illness/223950.
Code availability
The latest versions of Genomic SEM and E-SEM are publicly available software and can be accessed at https://github.com/GenomicSEM/GenomicSEM. The exact version of all software utilized in this study can be accessed at https://zenodo.org/records/17526988.
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Acknowledgments
J.M.L. is supported by NIMH Grant T32MH016880. A.D.G. and L.S.S. are supported by NIH Grant R01MH120219. A.D.G. and I.F.F. are supported by NIA Grant R01AG073593. T.T.M. is supported by NIH grant K08MH135343. S.B. is supported by the Shurl and Kay Curci Foundation. We acknowledge the Penn Medicine BioBank (PMBB) for providing data and thank the patient-participants of Penn Medicine who consented to participate in this research program. We would also like to thank the Penn Medicine BioBank team and Regeneron Genetics Center for providing genetic variant data for analysis. The PMBB is approved under IRB protocol# 813913 and supported by the Perelman School of Medicine at the University of Pennsylvania, a gift from the Smilow family, and the National Center for Advancing Translational Sciences of the National Institutes of Health under CTSA award number UL1TR001878.
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J.M.L., I.F.F., S.B., and A.D.G. conceived and designed the study. J.M.L. and S.A. undertook the statistical analysis. J.M.L. wrote the first draft of the paper. L.S.S., S.L., M.G.L., S.M.D., and T.T.M. contributed to data interpretation, offering significant intellectual contributions to the paper and its final approved version.
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S.M.D. receives research support from RenalytixAI and in-kind research support from Novo Nordisk, both outside the scope of the current project. The remaining authors declare no competing interests.
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Lawrence, J.M., Foote, I.F., Breunig, S. et al. Shared Genetic Liability across Systems of Psychiatric and Physical Illness. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69218-1
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DOI: https://doi.org/10.1038/s41467-026-69218-1
