We report a large meta-analysis of depression using data from the Million Veteran Program (MVP), 23andMe Inc., UK Biobank, and FinnGen; including individuals of European ancestry (n=1,154,267; 340,591 cases) and African ancestry (n=59,600; 25,843 cases). We identified 223 and 233 independent SNPs associated with depression in European ancestry and transancestral analysis, respectively. Genetic correlations within the MVP cohort across electronic health records diagnosis, survey self-report of diagnosis, and a 2-item depression screen exceeded 0.81. Using transcriptome-wide association study (TWAS) we found significant associations for gene expression in several brain regions, including hypothalamus (NEGR1, p=3.19x10-25) and nucleus accumbens (DRD2, p=1.87x10-20). 178 genomic risk loci were fine-mapped to find likely causal variants. We identified likely pathogenicity in these variants and overlapping gene expression for 17 genes from our TWAS, including TRAF3. This study sheds light on the genetic architecture of depression and provides new insight into the interrelatedness of complex psychiatric traits.

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