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Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions.

By David M Howard, Mark J Adams, T-K Clarke, Jonathan D. Hafferty, Jude Gibson, Masoud Shirali, Jonathan RI Coleman, Saskia P Hagenaars, Joey Ward, Eleanor M Wigmore, Clara Alloza, Xueyi Shen, Miruna C Barbu, Eileen Y. Xu, Heather C Whalley, Riccardo E. Marioni, David J. Porteous, Gail Davies, Ian J Deary, Gibran Hemani, Klaus Berger, Henning Teismann, Rajesh Rawal, Volker Arolt, Bernhard T Baune, Udo Dannlowski, Katharina Domschke, Chao Tian, David A. Hinds, 23andMe Research Team, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Maciej Trzaskowski, Enda M. Byrne, Stephan Ripke, Daniel J Smith, Patrick F Sullivan, Naomi R. Wray, Gerome Breen, Cathryn Lewis, Andrew McIntosh

Posted 09 Oct 2018
bioRxiv DOI: 10.1101/433367 (published DOI: 10.1038/s41593-018-0326-7)

Major depression is a debilitating psychiatric illness that is typically associated with low mood, anhedonia and a range of comorbidities. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximise sample size, we meta-analysed 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 gene-sets associated with depression, including both genes and gene-pathways associated with synaptic structure and neurotransmission. Further evidence of the importance of prefrontal brain regions in depression was provided by an enrichment analysis. 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 following multiple testing correction. Based on the putative genes associated with depression this work also highlights several potential drug repositioning opportunities. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding aetiology and developing new treatment approaches.

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