Multi-ethnic studies identify new genes for depression

Two significant international studies have revealed hundreds of previously unknown genetic links to depression, which could allow scientists to predict depression risk as well as pave the way for more effective drug treatments.

Depression is very common, yet how it develops is still poorly understood. Genetic research using big data has already uncovered dozens of genes associated with the condition, as well as new drug targets, but research so far has mainly focused on people of European ancestry, which is a major shortcoming for such a complex disorder.

Since 2017, a team led by King’s College London and The University of Edinburgh has analysed anonymised genetic data from more than five million people in 29 countries worldwide, one in four of whom came from non-European ancestries. Their findings, published in the journal Cell, identify 697 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. Furthermore, 100 of these variations were identified due to the inclusion of people of African, East Asian, Hispanic and South Asian descent.

The researchers said they were able to more accurately predict an individual’s risk of depression by taking into account the newly identified variants. They also highlighted existing drugs pregabalin and modafinil — used to treat chronic pain and narcolepsy, respectively — which could potentially be repurposed for the treatment of depression, based on their findings. They acknowledged however that further studies and clinical trials are needed to explore the potential of the drugs in patients with depression.

The second international study, led by University College London (UCL), meanwhile reviewed genetic data from 21 study cohorts across several countries and included nearly one million participants of African, East Asian, South Asian and Hispanic/Latin American descent. That study, which was published in Nature Genetics, identified more than 50 new genetic loci and 205 novel genes that are associated with depression.

The study authors said they have made major advances identifying genes that are linked to risk of depression, both for newly identified links and by strengthening prior evidence, and showcasing 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.

Other genes identified in the study may have biologically plausible links with depression, such as a gene linked to a neurotransmitter involved in goal-directed behaviour, and genes encoding a type of protein previously linked with multiple neurological conditions.

Surprisingly, the researchers found less overlap in the genetic hits for depression across ancestry groups than expected, at about 30%, which is less overlap than previously found for other traits and diseases. Therefore, it is even more important to study depression in diverse samples because some of the findings might be ancestry specific.

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