Shared Genetic Liability across Systems of Psychiatric and Physical Illness

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.