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An international research team led by the University of Edinburgh and King's College London, with the participation of the Central Institute of Mental Health in Mannheim, has identified new genetic risk factors for depression across all ethnic groups in a global study. The largest genetic study of its kind to date discovered around 300 previously unknown genetic links to the disease, opening up new perspectives for diagnosis and treatment. Data from more than five million people from 29 countries formed the basis for the results, which have now been published in the journal Cell.
The world's largest and most ethnically diverse genetic study of depression ever conducted has uncovered around 300 previously unknown links between genetic variations – small differences in the DNA sequence that makes up a gene – and the disease. This is the first time that new genetic risk factors for depression have been identified across all major world populations.
100 of the newly discovered genetic variations were identified by including people of African, East Asian, Hispanic and South Asian descent. The international study was conducted under the direction of the University of Edinburgh and King's College London and with the participation of the Central Institute of Mental Health (CIMH) in Mannheim.
More accurate prediction of depression risk
Previous research into the genetics of depression has focused primarily on populations originally descended from people living in Europe. Therapies developed based on genetic approaches may therefore not be effective in other ethnicities, which exacerbates current health inequalities.
Each individual genetic variant has a very small impact on the overall risk of developing depression. If a person has multiple variants, these small effects can add up and increase the risk. The research team was able to more accurately predict a person's risk of depression by taking into account the newly identified variants.
Around 300 unknown genetic correlations uncovered
The international team of scientists examined the genetic data of more than five million people in 29 countries worldwide. Every fourth person included in the study had non-European ancestors.
The researchers identified a total of 700 variations in the genetic code of individuals that are associated with the development of depression. Almost half of these variations, which relate to 308 specific genes, have never before been associated with the disease. The identified genetic variants have been linked to neurons, a type of brain cell, in different regions of the brain, including regions that control emotions.
New approaches for the treatment of depression possible
The results offer previously unknown insights into the causes of depression in the brain and could enable new approaches to treatment. The research team highlights the existing drugs pregabalin and modafinil, which are used to treat chronic pain and the sleep disorder narcolepsy respectively, and could potentially also be effective in the treatment of depression based on the study results. However, the team points out that further studies and clinical trials are needed to explore the potential of the drugs in patients with depression.
The study, which was funded by the National Institutes of Health (NIH)/USA, the German Federal Ministry of Education and Research (BMBF) and the German Research Foundation (DFG), among others, was published in the journal Cell.
Depression is highly polygenic
The Psychiatric Genomics Consortium research team involved scientists from all continents, including South Africa, Brazil, Mexico, the USA, Australia, Taiwan and China, in addition to the CIMH in Mannheim.
“There are huge gaps in our understanding of clinical depression that limit opportunities to improve outcomes for those affected. Larger and more globally representative studies are vital to provide the insights needed to develop new and better therapies, and prevent illness in those at higher risk of developing the condition,” said Prof. Andrew McIntosh, co-leader of the study and Professor at the University of Edinburgh's Centre for Clinical Brain Research.
“Depression is a highly prevalent disorder and we still have a lot to learn about its biological underpinnings. Our study identifies hundreds of additional genetic variants that play a role in depression. These findings show depression is highly polygenic and open up downstream pathways to translate these findings into better care for people with depression,” says Cathryn Lewis, co-leader of the study and Professor at the Institute of Psychiatry, Psychology & Neuroscience at King's College London.
“This study represents significant progress. However, there is a need to continue to identify genetic variants associated with psychiatric disorders in global populations. To close the gap between genetic discoveries and their clinical translation, we aim to develop and apply machine learning approaches to use multivariate polygenic risk score for predicting mental health conditions and response to specific treatments,” adds Dr. Fabian Streit, researcher at the Hector Institute for Artificial Intelligence in Psychiatry at the CIMH and one of the first authors of the study.
Publikation:
Andrew McIntosh et.al.: Trans-ancestry genome-wide study of depression identifies 697 associations implicating cell types and pharmacotherapies. In: Cell, January 14, 2025. DOI: 10.1016/j.cell.2024.12.002
https://www.cell.com/cell/fulltext/S0092-8674(24)01415-6
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