A global study led by UCLA researchers has identified more than 200 new genes linked to depression, paving the way for new treatments and highlighting the need for inclusive genetic research.

The study, published in the journal Nature Genetics, found more than 50 new genetic loci (a specific location on a chromosome) and 205 new genes associated with depression. It is the first large-scale, global study of the genetics of major depressive disorder in participants from different ancestry groups.

The study also demonstrates the potential for drug repurposing, as it identified a gene that codes for a protein targeted by a common diabetes drug, while also pointing to new targets for potential drugs to treat depression.

Genetic diversity in depression research

Depression is a very common disorder, but its pathogenesis remains poorly understood. Genetic research using big data is providing new ways to understand the disease and has identified dozens of genes linked to depression, each of which alone confer only a small increase in risk. It could also help find new drug targets, but studies so far have focused primarily on people of European ancestry, which researchers say is a significant shortcoming, especially for a disease as complex as depression.

The new paper used a variety of genetic research methods, including genome-wide association studies, a meta-analysis of previously published data, and transcriptome-wide association studies. The international team of researchers reviewed genetic data from 21 study cohorts from multiple countries, including nearly 1 million study participants of African, East Asian, South Asian and Hispanic/Latinx origin, including 88,316 patients with major depressive disorder.

This study makes significant progress in identifying genes associated with depression risk, both uncovering new links and strengthening previous evidence, and revealing some genes, such as NDUFAF3, that have potential implications for drug development. The protein encoded by NDUFAF3 has previously been implicated in mood instability, and metformin is a first-line treatment for type 2 diabetes. Animal studies of metformin have shown that it may be associated with reductions in depression and anxiety, so this latest finding further suggests that more research on metformin and depression may be necessary.

Other genes identified in the study may have biological links to depression, such as a gene related to a neurotransmitter involved in goal-directed behavior and a gene encoding a protein previously linked to a variety of neurological disorders.

Graph showing genome-wide genetic relatedness between African, European, East Asian, and Hispanic/Latin American populations. The shade of coloring reflects the strength of the correlation. The estimated coefficients and standard errors are also shown in each cell. We only show estimates with standard errors less than 0.3; otherwise, the area is grayed out.

New horizons in depression treatment

Surprisingly, the researchers found that the genetic hits for depression overlapped less than expected across different ancestral groups, at about 30% (according to a new method developed by the research team to measure the extent to which genetic associations found in one ancestral group hold true for another), which was less than the degree of overlap previously found in other traits and disorders. Therefore, it is even more important to study depression in diverse samples, as some findings may be ancestral-specific.

Lead author Professor Karoline Kuchenbaecker (UCL Psychiatry and UCL Institute of Genetics) said: "What we show here beyond doubt is that unless we overcome the Eurocentric bias in genetics research and look for causes in diverse populations around the world, our understanding of complex conditions such as depression will remain incomplete."

"Many genes previously linked to depression risk may actually only affect depression risk in people of European ancestry, so in order for genetic research to contribute to the development of new drugs that can help people of all ancestry, our genetic data sets must be appropriately diverse."

Professor Kuchenback co-led this research with Dr. Xiangrui Meng, doctoral researchers Georgina Navoly and Dr. Olga Giannakopoulou. The collaborative alliances involved in the research include the Psychiatric Genomics Consortium-Major Depressive Disorder Working Group, the China Kadoorie Biobank Collaboration Group, the 23andMe Research Team, the Genes and Health Research Team, and the Japanese Biodatabase Project.

Professor Kuchenbaecker added: "This is a first-stage discovery effort, so more work is needed to confirm these new targets, but finding these targets in the first place is a huge and important challenge, especially for a disease that is in dire need of new drug treatments."

Compiled source: ScitechDaily