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

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.

Minimal phenotyping yields GWAS hits of reduced specificity for major depression

“…We identified five ways that MDD can be defined in UKBiobank. First, using self-reports of seeking medical attention for depression or related conditions, we identified "Help-seeking" definitions of MDD (referred to as "broad depression" in a previous GWAS 3 ). Second, participants were diagnosed with "Symptom-based" MDD if, in addition to meeting the help seeking criteria described above, they reported ever experiencing one or more of the two cardinal features of depression (low mood or anhedonia) for at least two weeks (this is the "probable MDD" diagnosis available in UKBiobank 17 ).…”

“…However, apart from the detection of more and more GWAS loci [3][4][5] (Supplemental Table S1), the consequences of sacrificing symptomatic information for genetic analyses has rarely been investigated. The consequences may be particularly important for major depressive disorder (MDD) because of its phenotypic and likely etiological heterogeneity 6 , high degree of comorbidity with other psychiatric diseases 7 , and substantial discrepancies between self-assessment using symptom scales and diagnoses made with full diagnostic criteria 8 .…”

Genome‐wide association analysis of autism identified multiple loci that have been reported as strong signals for neuropsychiatric disorders

“…This locus is significant in Intelligence [Hill et al, ];Response to SSRI in MDD or openness [Amare et al, ]; Depression [Howard et al, ]; Schizophrenia [Amare et al, ; Howard et al, ];Cognitive performance [Lee et al, ]; Educational attainment (MTAG) [Lee et al, ]; General cognitive ability [Davies et al, ; Lee et al, ] in GWAS study.…”

Analyzing the genes and pathways related to major depressive disorder via a systems biology approach

“…Finally, several studies on MDD via GWA meta-analysis have been published recently (Howard et al, 2018(Howard et al, , 2019Wray et al, 2018). For such reason, the collected MDD-related genes may include a high fraction of genes also associated with other mental disorder, but we believe that with further improvement, the pathogenic genes for MDD will be supplemented and the dataset will become more and more reliable.…”

“…Although there are some shortcomings in the current study, we believe the results obtained by us should be reliable. Finally, several studies on MDD via GWA meta-analysis have been published recently (Howard et al, 2018(Howard et al, , 2019Wray et al, 2018).…”