In summary, we identified multiple novel loci, and several of these loci serve functions that should prioritize their further study in the pathology of major depression. We examined genetic correlations between depression GWAS and other external phenotypes, largely confirming and strengthening previous observations. We showed substantial enrichments for several brain regions, such as hypothalamus and frontal cortex, known to be important for depression. We also find strong support for the importance of DRD2 in the nucleus accumbens, a finding that is consistent with an emerging role for dopaminergic function in symptoms of anhedonia. Using gene and drug-based enrichments we found overlapping biology with existing drugs – notably those that impact glutamatergic function, but also those that influence the actions of estrogen – that could offer repurposing opportunities. We used genomic structural equation modeling to show how the genetic architecture of depression maps onto the broader genetic structure of mental disorders and cognition, identifying emergent overlap from hypothesis-free GWAS approaches with existing theories of psychopathology with regard to clusters of internalizing and externalizing disorders. Finally, we showed that many of our
