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Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways

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David M. Howard, Mark J. Adams, Masoud Shirali, Toni-Kim Clarke, Riccardo E. Marioni, Gail Davies, Jonathan R. I. Coleman, Clara Alloza, Xueyi Shen, Miruna C. Barbu, Eleanor M. Wigmore, Jude Gibson, Saskia P. Hagenaars, Cathryn M. Lewis, Joey Ward, Daniel J. Smith, Patrick F. Sullivan, Chris S. Haley, Gerome Breen, Ian J. Deary & 1 more Andrew M. McIntosh

Original languageEnglish
Article number1470
Number of pages10
JournalNature Communications
Volume9
Issue number1
Early online date16 Apr 2018
DOIs
Accepted/In press4 Aug 2017
E-pub ahead of print16 Apr 2018
Published16 Apr 2018

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Abstract

Depression is a polygenic trait that causes extensive periods of disability. Previous genetic studies have identified common risk variants which have progressively increased in number with increasing sample sizes of the respective studies. Here, we conduct a genome-wide association study in 322,580 UK Biobank participants for three depression-related phenotypes: broad depression, probable major depressive disorder (MDD), and International Classification of Diseases (ICD, version 9 or 10)-coded MDD. We identify 17 independent loci that are significantly associated (P < 5 × 10−8) across the three phenotypes. The direction of effect of these loci is consistently replicated in an independent sample, with 14 loci likely representing novel findings. Gene sets are enriched in excitatory neurotransmission, mechanosensory behaviour, post synapse, neuron spine and dendrite functions. Our findings suggest that broad depression is the most tractable UK Biobank phenotype for discovering genes and gene sets that further our understanding of the biological pathways underlying depression.

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