Depression affects approximately 15% of the world's population during their lifetime. It is one of the leading causes of disability worldwide. Psychotherapies combined with medication are effective, but responses to treatments vary greatly. A better understanding of the mechanisms underlying the disease would help develop more targeted therapies. To do this, a team carried out the largest and most comprehensive genome-wide association studies on depression.
This psychological illness results from a complex interaction of social, psychological and biological factors. Some people are more vulnerable than others. Certain life events lead to an increased risk of depression, but genetics also come into play. Research in twins and families has found a significant genetic contribution to the etiology of the disease, with a heritability of approximately 37%.
Five million individuals of diverse ancestry
Genome-wide association studies (GWAS) have provided insight into the genetic risk factors for depression and its underlying mechanisms. The largest study carried out to date included more than 1.3 million individuals, of whom 371,000 had depression. It highlighted 243 depression risk loci.
Despite these findings, the molecular, cellular, and neurobiological mechanisms of depression remain largely unidentified. Consequently, drug treatments based on these mechanisms remain few in number.
Thanks to a new genome-wide association study, including individuals of diverse origins, researchers have identified nearly 300 new genomic regions associated with depression. Credits: McIntosh et al., Cell (2025)
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To improve our overall understanding of the disease, the major depressive disorder working group of the Psychiatric Genomics Consortium undertook a meta-analysis of a GWAS involving five million individuals. They came from 29 countries and of diverse and mixed ancestry. Nearly 689,000 members of this cohort suffered from depression.
The researchers wanted to conduct the “largest and most inclusive” genetic study, they specify in the journal cell. Indeed, previous research into the genetics of depression has primarily focused on white populations, who were descended from people living in Europe. “ Therapies developed using genetic approaches may therefore not be effective in other ethnicities, exacerbating existing health inequalities », Explains a press release from King's College London.
In this new sample, one in four people was of non-European origin. “ Our final sample […] with diverse ancestry led to an increase in the discovery of genome-wide significant loci compared to analysis of European-only ancestry studies », note the researchers.
New genetic risk factors for depression
This greater diversity made it possible to identify 697 significant independent nucleotide polymorphisms, in 635 genomic regions. About half (293/635, or 46%) of the loci discovered had never been associated with the disease before. The researchers specify that the discovery of around a hundred of them results from the inclusion of non-European people.
The team also reports having identified 308 “high confidence” genetic associations. In other words, these genes were associated with a higher risk of depression. Note that each genetic variant has a very small effect on the overall risk of developing depression. But if an individual has several variants, their effects can add up and thus increase the risk.
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These genetic changes were linked to neurons in several brain regions, including those that control emotions. “ Importantly, the increased power of this genetic analysis provided additional evidence for the involvement of excitatory neurons in the amygdala and hippocampus, including granule cells and medium spiny neurons. », Specify the researchers.
These results significantly expand the findings of previous genome-wide association studies, implicating genes, cell types, and tissues in the etiology of depression. By identifying these new risk factors, scientists can predict depression more accurately. And this, whatever the ethnic origin.
Better understanding the impact of depression on the brain also allows us to identify new potential therapeutic targets. In addition to traditional antidepressants, other classes of medications have shown promise. The team mentions in particular several anticancer therapies, but also pregabalin (used for the treatment of chronic pain) and modafinil (used for daytime sleepiness caused by narcolepsy). These drugs could therefore potentially be repurposed to treat depression.
However, further studies and clinical trials are needed to explore the potential of these medications in depressed patients.
Towards personalized treatments for depression
“ These findings show that depression is highly polygenic and open downstream pathways to translate these findings into better care for people with depression said Cathryn Lewis, professor of genetic epidemiology and statistics at the Institute of Psychiatry, Psychology and Neuroscience at King's College and co-leader of the study.
Psychotherapies are first-line treatments for mild depression. In moderate to severe cases, they are accompanied by drug treatment (antidepressants). The combination of the two approaches is effective in most cases and prevents relapses. Responses to current treatments, however, vary greatly from one patient to another.
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Better understanding depression, particularly its genetic factors, could reveal new mechanisms linked to the development of the disease. From there new therapeutic targets would emerge. The ideal would be to have personalized treatments for each clinical profile, particularly for patients at high genetic risk.
“ There are huge gaps in our understanding of clinical depression that limit opportunities to improve outcomes for those affected. Larger, more globally representative studies are essential to provide the information needed to develop new and better therapies, and to prevent the disease in people who are at higher risk of developing it. “. concludes Andrew McIntosh, professor of biological psychiatry at the Center for Clinical Brain Sciences at the University of Edinburgh and co-director of the study.
Dr David Crepaz-Keay, director of research at the Mental Health Foundation, nevertheless believes that genetic risk should not be used as a “definitive guide” to treating depression. “ LDepression prevention should focus on addressing larger issues in society that have a much greater impact on mental health, such as experiences of poverty or racism. “, he declared to the Guardian.
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