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

Depression is a polygenic trait that causes extensive periods of disability. Previous genetic studies have identi fi ed 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 Classi fi cation of Diseases (ICD, version 9 or 10)-coded MDD. We identify 17 independent loci that are signi fi cantly 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 fi ndings. Gene sets are enriched in excitatory neurotransmission, mechanosensory behaviour, post synapse, neuron spine and dendrite functions. Our fi ndings 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.