A groundbreaking study has uncovered more than 200 genes linked to depression, shedding light on the complex nature of the condition, offering potential drug targets and insights into its development. Importantly, it emphasises the need for diverse genetic datasets to better understand and treat this widespread mental health disorder.
The research, published in Nature Genetics, found more than 50 new genetic loci (a locus is a specific position on a chromosome) and 205 novel genes that are associated with depression in the first large-scale global study of the genetics of major depression in participants of diverse ancestry groups.
The study also showcases the potential for drug repurposing, as one of the identified genes encodes a protein targeted by a common diabetes drug, while also pointing to new targets for drugs that may be developed to treat depression.
Depression is very common, yet how it develops is still poorly understood. Genetic research using big data offers new avenues to understand the disease and has uncovered dozens of genes associated with depression, each of which individually confers only a small increase in risk.
It can also help find new drug targets, but so far, research has mainly focused on people of European ancestry, which the researchers say is a major shortcoming, especially for such a complex condition as depression.
The international research team reviewed genetic data from 21 study cohorts from several countries and included nearly one million study participants of African, East Asian, South Asian, and Hispanic/Latin American descent, including 88,316 people with major depression.
The study has made major advances in identifying genes that are linked to the risk of depression, both for newly identified links and by strengthening prior evidence, and showcases some genes with potential implications for drug development, such as NDUFAF3.
The protein that NDUFAF3 encodes has been implicated previously in mood instability, and it is targeted by metformin, the first-line drug for treating type 2 diabetes. Animal studies of metformin have suggested a possible link with reduced depression and anxiety, so this latest finding further suggests that additional research into metformin and depression may be warranted.
Surprisingly, the researchers found less overlap in the genetic hits for depression across ancestry groups than expected, at about 30% (based on a new method developed by the research team to gauge the degree to which a genetic association found in one ancestry group is applicable to another ancestry group), which is less overlap than previously found for other traits and diseases.
Lead author Professor Karoline Kuchenbaecker (UCL Psychiatry and UCL Genetics Institute) said, “Here we show beyond doubt that our understanding of such complex diseases as depression will remain incomplete until we overcome the Eurocentric bias in genetics research and look for causes in diverse people across the world.”