Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions.
Howard DM., Adams MJ., Clarke T-K., Hafferty JD., Gibson J., Shirali M., Coleman JRI., Hagenaars SP., Ward J., Wigmore EM., Alloza C., Shen X., Barbu MC., Xu EY., Whalley HC., Marioni RE., Porteous DJ., Davies G., Deary IJ., Hemani G., Berger K., Teismann H., Rawal R., Arolt V., Baune BT., Dannlowski U., Domschke K., Tian C., Hinds DA., 23andMe Research Team None., Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium None., Trzaskowski M., Byrne EM., Ripke S., Smith DJ., Sullivan PF., Wray NR., Breen G., Lewis CM., McIntosh AM.
Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximize sample size, we meta-analyzed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 genesets associated with depression, including both genes and gene pathways associated with synaptic structure and neurotransmission. An enrichment analysis provided further evidence of the importance of prefrontal brain regions. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant after multiple testing correction. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding etiology and developing new treatment approaches.