Schematic diagram of the analyzes in this study. We included data from 21 cohorts of diverse ancestry. We divided individuals into ancestry/ethnic groups and performed association analyzes with MD for each. Subsequently, we meta-analyzed the results by ancestry/ethnic group. We tested whether MD loci previously reported in European ancestry studies were transferable to these groups. We also used the results to uncover novel associations of depression and MR to assess the causal effects of cardiometabolic traits by ancestry. We then merged all ancestry/ethnicity-specific results into a multi-ancestry meta-analysis including samples of European ancestry. The results of the multi-bottom-up meta-analysis provided the basis for locus discovery, fine mapping to identify causal variants, and several gene prioritization approaches to identify genes linked to DM risk. ST.(not) refers to the corresponding supplementary table. ST.2* (in green) refers to Supplementary Table 2, showing genomic inflation estimates from multiple analyses. Credit: Natural genetics (2024). DOI: 10.1038/s41588-023-01596-4
More than 200 genes linked to depression have been newly identified in a global study led by UCL researchers.
The research, published in Natural geneticsdiscovered more than 50 new genetic loci (a locus is a specific position on a chromosome) and 205 new genes associated with depression in the world’s first large-scale study of the genetics of major depression in participants from diverse groups of ancestry.
The study also presents the potential for drug repurposing, as one of the identified genes encodes a protein targeted by a common diabetes drug, while also pointing to new targets for drugs that could be developed to treat depression.
Depression is very common, but its development remains poorly understood. Genetic research using big data offers new avenues for understanding the disease and has discovered dozens of genes associated with depression, each of which confers only a slight increase in risk. It may also help find new drug targets, but so far research has primarily focused on people of European ancestry, which researchers say is a major gap, especially for a disease so complex than depression.
The new paper involved several genetic research methods, including genome-wide association studies, a meta-analysis of previously published data, and a transcriptome-wide association study. The international research team examined genetic data from 21 study cohorts from multiple countries and included nearly one million study participants of African, East Asian, South Asian and Hispanic/American descent. Latin America, including 88,316 people suffering from major depression.
The study made major advances in identifying genes linked to depression risk, both for newly identified links and by strengthening previous evidence, and highlights some genes with potential implications for drug development , such as NDUFAF3.
The protein encoded by NDUFAF3 has previously been implicated in mood instability and is targeted by metformin, the first-line drug to treat type 2 diabetes. Animal studies of metformin have suggested a possible link with reduction of depression and anxiety. These latest findings therefore suggest that additional research into metformin and depression may be warranted.
Other genes identified in the study may have biologically plausible links to depression, such as a gene linked to a neurotransmitter involved in goal-directed behavior and genes encoding a type of protein previously linked to several neurological conditions.
Surprisingly, the researchers found less overlap than expected in the genetic impacts of depression between ancestry groups, at about 30% (based on a new method developed by the research team to assess the degree to which a genetic association found in one ancestry group is applicable to another ancestry group), representing less overlap than previously found for other traits and diseases.
Therefore, it is even more important to study depression in diverse samples, as some findings might be ancestry specific.
Lead author Professor Karoline Kuchenbaecker (UCL Psychiatry and UCL Genetics Institute) said: “Here we show beyond doubt that our understanding of diseases as complex as depression will remain incomplete until we overcome Eurocentric bias. in genetics research and looked for causes in various people around the world. the world.”
“Many genes previously associated with depression risk may only affect depression risk in people of European descent. Therefore, for genetic research to contribute to new drugs that can help people of all origins, it It is essential that our genetic datasets are sufficiently diverse.
Professor Kuchenbaecker added: “This is a first-stage discovery effort, so further work will be needed to confirm these new targets, but finding them in the first place has been a huge and vital challenge, particularly for a disorder where there are so many new medications. urgent need.”
More information:
Xiangrui Meng et al, A genome-wide multi-ascending association study of major depression facilitates locus discovery, fine mapping, gene prioritization and causal inference, Natural genetics (2024). DOI: 10.1038/s41588-023-01596-4
Provided by University College London
Quote: Newly identified genes for depression could lead to new treatments (January 10, 2024) retrieved January 10, 2024 from
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