Characterizing the phenotypic and genetic structure of psychopathology in UK Biobank

Mental health conditions are characterized by higher-order transdiagnostic factor structures, which may contribute to the high levels of comorbidity observed in psychopathology. However, the phenotypic and genetic structures of various psychopathology diagnoses may differ, raising questions about the validity and utility of these factors. Here we study the phenotypic and genetic factor structures of ten psychiatric conditions using UK Biobank and public genomic data. Although the factor structure of psychopathology was generally genetically and phenotypically consistent, conditions related to externalizing (for example, alcohol use disorder) and compulsivity (for example, eating disorders) exhibited cross-level disparities in their relationships with other conditions, possibly due to environmental influences. Domain-level factors, especially thought disorder and internalizing factors, were more informative than a general psychopathology factor in genome-wide association and polygenic index analyses. Collectively, our findings enhance the understanding of comorbidity and shared etiology, highlight the intricate interplay between genes and environment, and offer guidance for psychiatric research using polygenic indices. In this study using UK Biobank and genomic data, the phenotypic and genetic factor structures across ten psychiatric conditions are analyzed, finding general genetic and phenotypic consistency but greater potential gene and environment disparities in conditions associated with externalizing disorders.