Researchers say they have identified new genetic risk factors for depression across all major global populations for the first time, thus allowing scientists to predict the risk of depression regardless of ethnicity. The world’s largest and most diverse genetic study ever into major depression has revealed nearly 300 previously unknown genetic links to the condition, experts point out.
One hundred of the newly discovered genetic variations were identified due to the inclusion of people of African, East Asian, Hispanic, and South Asian descent, the study “Trans-ancestry genome-wide study of depression identifies 697 associations implicating cell-types and pharmacotherapies,” which was published in Cell, found.
“In a genome-wide association study (GWAS) meta-analysis of 688,808 individuals with major depression (MD) and 4,364,225 controls from 29 countries across diverse and admixed ancestries, we identify 697 associations at 635 loci, 293 of which are novel. Using fine-mapping and functional tools, we find 308 high-confidence gene associations and enrichment of postsynaptic density and receptor clustering,” wrote the investigators.
“A neural cell-type enrichment analysis utilizing single-cell data implicates excitatory, inhibitory, and medium spiny neurons and the involvement of amygdala neurons in both mouse and human single-cell analyses. The associations are enriched for antidepressant targets and provide potential repurposing opportunities. Polygenic scores trained using European or multi-ancestry data predicted MD status across all ancestries, explaining up to 5.8% of MD liability variance in Europeans.
“These findings advance our global understanding of MD and reveal biological targets that may be used to target and develop pharmacotherapies addressing the unmet need for effective treatment.”
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 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 was 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 anonymized 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. They 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. The findings offer new insight into depression’s impact on the brain and present possible new targets for treatment, experts say.
The research team highlights 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 cautions that further studies and clinical trials are needed to explore the potential of the drugs in patients with depression.
“There are huge gaps in our understanding of clinical depression that limit opportunities to improve outcomes for those affected,” noted Andrew McIntosh, PhD, study co-lead, from the University of Edinburgh’s Centre for Clinical Brain Sciences. “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.”
“Depression is a highly prevalent disorder, and we still have a lot to learn about its biological underpinnings,” added Cathryn Lewis, PhD, study co-lead, from the Institute of Psychiatry, Psychology & Neuroscience at King’s College London. “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.”
The research team from the Psychiatric Genomics Consortium involved scientists from all continents, including studies from South Africa, Brazil, Mexico, the U.S., Australia, Taiwan, and China.
