Bi-Ancestral Depression GWAS in the Million Veteran Program and Meta-Analysis in >1.2 Million Subjects Highlights New Therapeutic Directions

• Published in: Nature neuroscience 2021-05, Vol.24 (7), p.954-963
• Main Authors: Levey, Daniel F., Stein, Murray B., Wendt, Frank R., Pathak, Gita A., Zhou, Hang, Aslan, Mihaela, Quaden, Rachel, Harrington, Kelly M., Nuñez, Yaira Z., Overstreet, Cassie, Radhakrishnan, Krishnan, Sanacora, Gerard, McIntosh, Andrew M., Shi, Jingchunzi, Shringarpure, Suyash S., Concato, John, Polimanti, Renato, Gelernter, Joel
• Format: Article
• Language: English
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/s41593-021-00860-2

Major depressive disorder is the most common neuropsychiatric disorder, affecting 11% of veterans. We report results of 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). Transcriptome-wide association study (TWAS) analyses revealed significant associations with expression of NEGR1 in the hypothalamus and DRD2 in the nucleus accumbens, among others. 178 genomic risk loci were fine-mapped, and we identified likely pathogenicity in these variants and overlapping gene expression for 17 genes from our TWAS, including TRAF3 . Finally, we were able to show substantial replications of our findings in a large independent cohort (N=1,342,778) provided by 23andMe. This study sheds light on the genetic architecture of depression and provides new insight into the interrelatedness of complex psychiatric traits.