Multivariate GWAS of psychiatric disorders and their cardinal symptoms reveal two dimensions of cross-cutting genetic liabilities

Understanding which biological pathways are specific versus general across diagnostic categories and levels of symptom severity is critical to improving nosology and treatment of psychopathology. Here, we combine transdiagnostic and dimensional approaches to genetic discovery for the first time, conducting a novel multivariate genome-wide association study of eight psychiatric symptoms and disorders broadly related to mood disturbance and psychosis. We identify two transdiagnostic genetic liabilities that distinguish between common forms of psychopathology versus rarer forms of serious mental illness. Biological annotation revealed divergent genetic architectures that differentially implicated prenatal neurodevelopment and neuronal function and regulation. These findings inform psychiatric nosology and biological models of psychopathology, as they suggest that the severity of mood and psychotic symptoms present in serious mental illness may reflect a difference in kind rather than merely in degree. [Display omitted] •Identification of two dimensions of genetic risk in mood and psychotic psychopathology•Pleiotropic genes broadly implicate neuronal pathways in psychopathology•Dimensions of genetic risk differ in their associations with health and disease Mallard et al. identified two transdiagnostic dimensions of genetic risk in a large genome-wide association study of psychiatric phenotypes related to mood disturbance and psychosis. While these genetic risk factors were modestly correlated, they were largely unique from one another and differed in their relationships with health and wellbeing.