Health UK (Commonwealth Union) – University College London (UCL) researchers, leading a worldwide study, have identified over 200 genes associated with depression. Published in Nature Genetics, the research marks the first extensive global investigation into the genetics of major depression across diverse ancestry groups, revealing more than 50 new genetic loci and 205 novel genes linked to the condition. The study suggests potential for drug repurposing, highlighting a gene encoding a protein targeted by a common diabetes drug and identifying new drug targets for depression treatment.
Researchers of the study highlighted the fact that despite its prevalence, the development of depression remains poorly understood. Utilizing big data for genetic research provides fresh insights into the disease, uncovering numerous genes associated with depression, each conferring only a slight increase in risk individually. The study underscores the importance of addressing the major shortcoming of past research, which predominantly focused on individuals of European ancestry. The complexity of depression calls for a more inclusive approach.
Employing various genetic research methods, including genome-wide association studies and meta-analysis of existing data, the international research team conducted a transcriptome-wide association study. Analyzing genetic data from 21 study cohorts across multiple countries, the study encompassed nearly one million participants of African, East Asian, South Asian, and Hispanic/Latin American descent, featuring 88,316 individuals with major depression.
The study has achieved significant progress in identifying genes associated with the risk of depression, both by uncovering new links and strengthening existing evidence. Notably, it highlights certain genes, including NDUFAF3, which holds potential implications for drug development. The protein encoded by NDUFAF3 has previously been implicated in mood instability and is targeted by metformin, the primary drug for type 2 diabetes. Previous animal studies on metformin have hinted at a potential connection with reduced depression and anxiety, suggesting the need for further exploration into the relationship between metformin and depression.
Researchers of the study also pointed out that several other genes identified demonstrate biologically plausible connections with depression. For instance, a gene linked to a neurotransmitter involved in goal-directed behavior and genes encoding a specific type of protein previously associated with various neurological conditions are among the findings.
Interestingly, the study reveals a lower-than-expected overlap in genetic associations for depression across different ancestry groups, approximately 30%, as assessed by a novel method developed by the research team. This finding underscores the importance of diversifying research samples for depression, as certain genetic associations may be specific to particular ancestry groups. This contrasts with previous observations for other traits and diseases, highlighting the unique genetic landscape of depression across different populations.
Lead author Professor Karoline Kuchenbaecker of the UCL Psychiatry and UCL Genetics Institute says “Here we show beyond doubt that our understanding of such complex diseases as depression will remain incomplete until we overcome the Eurocentric bias in genetics research and look for causes in diverse people across the world.
“Many genes previously found to be linked to the risk of depression might only actually affect depression risk in people of European origin, so in order for genetic research to contribute to new drugs that can help people of all ancestries, it is vital that our genetic datasets are suitably diverse.”
Professor Kuchenbaecker who was the lead of the study together with Dr Xiangrui Meng, PhD researcher Georgina Navoly as well as Dr Olga Giannakopoulou, together with the collaborative consortia taking part in the research consisted of the Psychiatric Genomics Consortium-Major Depressive Disorder Working Group, China Kadoorie Biobank Collaborative Group, the 23andMe Research Team, Genes and Health Research Team, plus the BioBank Japan Project.
The findings are likely to provide key insights for the treatment of depression.
