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

Howard, D. M. et al. (2019) Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nature Neuroscience, 22, pp. 343-352. (doi: 10.1038/s41593-018-0326-7) (PMID:30718901)

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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.

Item Type:Articles
Additional Information:Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) Reference 104036/Z/14/Z). A.M.McI and I.J.D. acknowledge support from the Wellcome Trust (Wellcome Trust Strategic Award ‘STratifying Resilience and Depression Longitudinally’ (STRADL) Reference 104036/Z/14/Z and the Dr Mortimer and Theresa Sackler Foundation. I.J.D. is supported by the Centre for Cognitive Ageing and Cognitive Epidemiology, which is funded by the Medical Research Council and the Biotechnology and Biological Sciences Research Council (MR/K026992/1). This investigation represents independent research part-funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. G.H. is supported by the Wellcome Trust (208806/Z/17/Z). D.J.S. is supported by the Lister Institute Prize Fellowship 2016-2021. N.R.W. acknowledges NMHRC grants 1078901 and 1087889. The BiDirect Study is supported by grants of the German Ministry of Research and Education (BMBF) to the University of Münster (01ER0816 and 01ER1506). The Münster cohort was funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5-2 to U.D.; SFB-TRR58, Projects C09 and Z02 to U.D.) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to U.D.). The PGC has received major funding from the US National Institute of Mental Health and the US National Institute of Drug Abuse (U01 MH109528 and U01 MH1095320).
Glasgow Author(s) Enlighten ID:Smith, Professor Daniel and Ward, Dr Joey
Authors: Howard, D. M., Adams, M. J., Clarke, T.-K., Hafferty, J. D., Gibson, J., Shirali, M., Coleman, J. R. I., Hagenaars, S. P., Ward, J., Wigmore, E. M., Alloza, C., Shen, X., Barbu, M. C., Xu, E. Y., Whalley, H. C., Marioni, R. E., Porteous, D. J., Davies, G., Deary, I. J., Hemani, G., Berger, K., Teismann, H., Rawal, R., Arolt, V., Baune, B. T., Dannlowski, U., Domschke, K., Tian, C., Hinds, D. A., Trzaskowski, M., Byrne, E. M., Ripke, S., Smith, D. J., Sullivan, P. F., Wray, N. R., Breen, G., Lewis, C. M., and McIntosh, A. M.
College/School:College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Mental Health and Wellbeing
Journal Name:Nature Neuroscience
Publisher:Nature Publishing Group
ISSN (Online):1546-1726
Published Online:04 February 2019
Copyright Holders:Copyright © 2019 The Authors, under exclusive licence to Springer Nature America, Inc.
First Published:First published in Nature Neuroscience 22:343-352

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190082Generation ScotlandAnna DominiczakChief Scientist Office (CSO)CZD/16/6MVLS - College Senior Management