New genetic risk factors for depression have been identified across all major global populations for the first time, allowing scientists to predict risk of depression regardless of ethnicity. A research team led by Professor Andrew McIntosh and including Generation Scotland's Dr Mark Adams, Dr Xueyi Shen and Dr Pippa Thompson of the Institute of Genetics and Cancer have conducted the world’s largest and most diverse genetic study ever into major depression. This study has revealed nearly 300 previously unknown genetic links to the condition, experts say. This significant research is the largest of its kind, combining data from 93 studies, including the Generation Scotland study. Dr Mark Adams, lead analyst of this study, is Senior Bioinformatician for Generation Scotland. Volunteers from Generation Scotland played a vital role, contributing to the diverse data which helped researchers uncover critical insights into the genetic and biological factors underlying depression. 100 of the newly discovered genetic variations – small differences in the DNA sequence that makes up a gene – were identified due to the inclusion of people of African, East Asian, Hispanic and South Asian descent, the study found. Previous research into the genetics of depression has focused primarily on white populations that originally descended from people living in Europe. Therapies developed using genetic approaches may therefore not be effective in other ethnicities, widening existing health inequalities.Each single genetic variant has a very small effect on the overall risk of developing depression. If a person has multiple variants, these small effects can add up, increasing their risk. The research team were able to more accurately predict an individual’s risk of depression by taking into account the newly identified variants.The international team of scientists, led by the University of Edinburgh and King’s College London, looked at anonymised genetic data from more than five million people in 29 countries worldwide. One in four individuals included in the study were from non-European ancestries. This is the largest and most inclusive genetic study of a psychiatric disorder to date, using data from across the globe on over half a million people who are affected by depression. Our findings have identified much more specific brain regions implicated in the biology of depression, and the challenge now is to determine which of these insights can be translated into better treatments. Dr Mark Adams Senior Bioinformatician for Generation Scotland and lead analyst of the new study Researchers identified a total of 700 variations in the genetic code of individuals linked to the development of depression, almost half of which had never been associated with the condition before, implicating 308 specific genes.The identified genetic variants were linked to neurons – a type of brain cell – across multiple brain regions, including areas which control emotion. The findings offer new insight into depression’s impact on the brain and present possible new targets for treatment, experts say.The research team highlight the existing drugs pregabalin and modafinil – used to treat chronic pain and the sleeping condition narcolepsy, respectively – which could potentially be repurposed for the treatment of depression, based on the study findings. However, the team caution that further studies and clinical trials are needed to explore the potential of the drugs in patients with depression.The study, funded by NIH, Wellcome and the National Institute for Health and Care Research Maudsley Biomedical Research Centre, is published in the journal Cell Link to the paper in Cell The research team from the Pyschiatric Genomics Consortium involved scientists from all continents, including studies from South Africa, Brazil, Mexico, the USA, Australia, Taiwan and China. 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. Professor Andrew McIntosh Study co-lead from the University of Edinburgh's Centre for Clinical Brain Sciences 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. Professor Cathryn Lewis Study co-lead from the Institute of Psychiatry, Psychology & Neuroscience at King's College London Generation Scotland, with its combination of mental health, biomarker, and health record data, will be an important resource in further research to understand exactly how the genetic differences identified contribute to depression.Generation Scotland serves as a vital bridge between volunteers and top scientists, driving efforts to improve the understanding, prevention and treatment of various health conditions. With over 40,000 volunteers, the study focuses on topics including mental health, loneliness, the impacts of lockdown, cancer, dementia, diabetes, reproductive health and many more. All of this research is made possible with the data provided by volunteers. To continue advancing health research, Generation Scotland is currently recruiting participants, and is open to anyone aged 12+ living in Scotland, aiming to represent the country's diversity.For more information and to join the study, visit www.gen.scot It is wonderful to see the Generation Scotland project continuing to contribute to worldwide efforts to understand the biological basis of depression. Such research holds the promise of identifying treatments that reduce the impact of this terrible condition on individuals, families and the wider community. Dr Pippa Thompson Institute of Genetics and Cancer, University of Edinburgh This article was published on 2025-01-14
