Global study on depression identifies new genetic risk factors

Scientists have identified new genetic risk factors for depression across all major global populations after a study involving five million participants, giving hope for new treatments.

The world’s largest and most diverse genetic study into depression revealed nearly 300 previously unknown genetic links.

A total of 100 of the newly discovered genetic variations – small differences in the DNA sequence that makes up a gene – were identified thanks to the inclusion of people of African, East Asian, Hispanic and South Asian descent.

Researchers from the University of Edinburgh and King’s College London studied anonymised genetic data from more than five million people in 29 countries, and believe the findings offer new insight into the impact of depression on the brain and present possible new targets for treatment.

One in four participants were from non-European ancestries, however, previous research into the genetics of depression focused primarily on white populations, originally descended from people living in Europe.

Scientists believe therapies developed using genetic approaches may not be effective in other ethnicities, widening health inequalities.

Each genetic variant has a very small effect on the overall risk of developing depression, however, if a person has multiple variants, these small effects can add up, increasing their risk, according to the study.

The research team was able to more accurately predict an individual’s risk of depression by taking into account newly identified variants, the study found.

The team 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 across multiple brain regions, including areas which control emotion, offering new insight into the condition and possible new treatment targets.

Existing drugs Pregabalin, used for chronic pain, and Modafinil, used for narcolepsy, could potentially be repurposed for the treatment of depression.

However, the team warned further studies and clinical trials would be needed to explore the potential of the drugs in patients with depression.

The research team from the Psychiatric Genomics Consortium involved scientists from all continents, including studies from South Africa, Brazil, Mexico, the US, Australia, Taiwan and China.

Professor Andrew McIntosh, study co-lead, from the University of Edinburgh’s Centre for Clinical Brain Sciences, said: “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 Cathryn Lewis, study co-lead, from the Institute of Psychiatry, Psychology and Neuroscience at King’s College London, said: “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 Veena Kumari, cognitive and clinical neuroscience expert at Brunel University of London’s Centre for Cognitive and Clinical Neuroscience, said:  “It’s one of the largest studies to date and, unlike many previous studies includes non-European samples as well. It has also identified many novel genetic variations linked to depression.

“These findings may inform further development of biological therapies for depression. Genetic studies in diverse global populations may or may not be fully applicable to certain ethnocultural groups.

“The genetic links identified here absolutely do not mean depression is inevitable for some people. Most of the genetic variants identified have only a small effect and confer a vulnerability to depression when there’s environmental stressors and risk factors such as abuse.

“Depression is a common problem with one in two people likely to experience it some point in their lifetime. Recovery typically requires a combination of drug and psychological therapies along with lifestyle changes.”

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: www.cell.com/cell/fulltext/S0092-8674(24)01415-6