Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions

• Published in: Nature neuroscience 2021-07, 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
• Subjects: 631/208/1515; 631/208/205/2138; 692/699/476/1414; Animal Genetics and Genomics; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Depressive Disorder, Major - genetics; Dopamine D2 receptors; Female; Gene expression; Genetic aspects; Genetic Predisposition to Disease - genetics; Genome-wide association studies; Genome-Wide Association Study; Health aspects; Humans; Hypothalamus; Major depressive disorder; Male; Mental depression; Mental disorders; Meta-analysis; Neurobiology; Neurosciences; Nucleus accumbens; Pathogenicity; Pathogens; Psychiatric research; Psychological aspects; Risk factors; Statistics; Systematic review; Transcriptomes; Veterans
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/s41593-021-00860-2

Major depressive disorder is the most common neuropsychiatric disorder, affecting 11% of veterans. Here we report results of a large meta-analysis of depression using data from the Million Veteran Program, 23andMe, 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 analyses revealed significant associations with expression of NEGR1 in the hypothalamus and DRD2 in the nucleus accumbens, among others. We fine-mapped 178 genomic risk loci, and we identified likely pathogenicity in these variants and overlapping gene expression for 17 genes from our transcriptome-wide association study, 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. This bi-ancestral genome-wide association study of major depressive disorder (MDD) identified 178 risk variants. The results advance understanding of the biology of MDD and hint at new treatment possibilities.