Psychiatric disorders display high levels of comorbidity and genetic overlap^1,2. Genomic methods have shown that even for schizophrenia and bipolar disorder, two disorders long-thought to be etiologically distinct³, the majority of genetic signal is shared⁴. Furthermore, recent cross-disorder analyses have uncovered over a hundred pleiotropic loci shared across eight disorders⁵. However, the full scope of shared and disorder-specific genetic basis of psychopathology remains largely uncharted. Here, we address this gap by triangulating across a suite of cutting-edge statistical genetic and functional genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders (1,056,201 cases). Our analyses identify and characterize five underlying genomic factors⁶ that explain the majority of the genetic variance of the individual disorders (~66% on average) and are associated with 268 pleiotropic loci. We observed particularly high levels of polygenic overlap⁷ and local genetic correlation⁸ and very few disorder-specific loci⁹ for two factors defined by: (i) schizophrenia and bipolar disorder ("SB factor"), and by (ii) major depression, PTSD, and anxiety ("internalizing factor"). At the functional level, we applied multiple methods^10-12 which demonstrated that the shared genetic signal across the SB factor was substantially enriched in genes expressed in excitatory neurons, whereas the internalizing factor was associated with oligodendrocyte biology. By comparison, the genetic signal shared across all 14 disorders was enriched for broad biological processes (e.g., transcriptional regulation). These results indicate increasing differentiation of biological function at different levels of shared cross-disorder risk, from quite general vulnerability to more specific pathways associated with subsets of disorders. These observations may inform a more neurobiologically valid psychiatric nosology and implicate novel targets for therapeutic developments designed to treat commonly occurring comorbid presentations.

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