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 maximise sample size, we meta-analysed 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 gene-sets 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 following multiple testing correction. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding aetiology and developing new treatment approaches.

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest GWAS to date of DSM-IV diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case/control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, N = 46,568; African; N = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; p = 9.8E-13) and African ancestries (rs2066702; p = 2.2E-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, ADHD, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and non-pathological drinking behaviors.

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.

Background: The coronavirus disease 2019 (COVID-19) pandemic and mitigation measures are likely to have a marked effect on mental health. It is important to use longitudinal data to improve inferences. Aims: To quantify the prevalence of depression, anxiety and mental wellbeing before and during the COVID-19 pandemic. To identify groups at risk of depression and/or anxiety during the pandemic. Methods: Data were from two generations of the Avon Longitudinal Study of Parents and Children (ALSPAC): the index generation (ALSPAC-young, n=2850, mean age=28), parent's generation (ALSPAC-parents, n=3720, mean age=59), and Generation Scotland (GS, n=4233, mean age=59). Depression was measured using the Short Mood and Feelings Questionnaire (SMFQ) in ALSPAC and the Patient Health Questionnaire (PHQ-9) in GS. Anxiety and mental wellbeing were measured using the Generalised Anxiety Disorder Assessment (GAD-7) and the Short Warwick Edinburgh Mental Wellbeing Scale. Results: Depression during COVID-19 was similar to pre-pandemic levels in ALSPAC-young, but those experiencing anxiety almost doubled during COVID-19: 24% (95% CI: 23%, 26%) compared to pre-pandemic levels of 13% (95% CI: 12%, 14%). In both ALSPAC and Generation Scotland, anxiety and depression during COVID-19 was greater in younger members, in women, in those with preexisting mental/physical health conditions, and in individuals in socioeconomic adversity, even when controlling for pre-pandemic anxiety and depression. Conclusions: These results provide evidence for increased anxiety in young people that is coincident with the pandemic. Specific groups are at elevated risk of depression and anxiety during COVID-19. This is important for planning mental health provisions now and for long-term impact beyond this pandemic.