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Genome-wide association study of depression phenotypes in UK Biobank (n = 322,580) identifies the enrichment of variants in excitatory synaptic pathways

By 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 Hagenaars, Cathryn M. Lewis, Daniel J. Smith, Patrick F Sullivan, Chris S. Haley, Gerome Breen, Ian Deary, Andrew M. McIntosh

Posted 27 Jul 2017
bioRxiv DOI: 10.1101/168732 (published DOI: 10.1038/s41467-018-03819-3)

Depression is a polygenic trait that causes extensive periods of disability and increases the risk of suicide, a leading cause of death in young people. Previous genetic studies have identified a number of common risk variants which have increased in number in line with increasing sample sizes. We conducted a genome-wide association study (GWAS) in the largest single population-based cohort to date, UK Biobank. This allowed us to estimate the effects of ≈ 8 million genetic variants in 320,000 people for three depression phenotypes: broad depression, probable major depressive disorder (MDD), and International Classification of Diseases (ICD, version 9 or 10)-coded MDD. Each phenotype was found to be significantly genetically correlated with the results from a previous independent study of clinically defined MDD. We identified 14 independent loci that were significantly associated (P < 5 × 10-8) with broad depression, two independent variants for probable MDD, and one independent variant for ICD-coded MDD. Gene-based analysis of our GWAS results with MAGMA revealed 46 regions significantly associated (P < 2.77 × 10-6) with broad depression, two significant regions for probable MDD and one significant region for ICD-coded MDD. Gene region-based analysis of our GWAS results with MAGMA revealed 59 regions significantly associated (P < 6.02 × 10-6) with broad depression, of which 27 were also detected by gene-based analysis. Variants for broad depression were enriched in pathways for excitatory neurotransmission, mechanosensory behavior, postsynapse, neuron spine and dendrite. This study provides a number of novel genetic risk variants that can be leveraged to elucidate the mechanisms of MDD and low mood.

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