The ERC grant enabled us to build the AnDi resource which includes 21 study cohorts from several countries and included nearly one million participants of African, East Asian, South Asian, and Hispanic/Latin American descent, including 88,316 people with major depression.
We applied state of the art methods that we and others developed to study the genetic basis of depression which significantly advanced our understanding of the mechanisms of this disease and offers exciting new paths for treatment.
Our research, published in the leading genetics journal Nature Genetics, found more than 50 new genetic loci 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 (Meng et al, 2024, Nature Genetics).
The study also showcases 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.
The study has made major advances identifying genes that are linked to 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.
Other genes we identified 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, we found less overlap in the genetic hits for depression across ancestry groups than expected, at about 30% (based on our new method 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. Therefore, it is even more important to study depression in diverse samples because some of the findings might be ancestry specific.
Cardiovascular disease is more prevalent in patients with depression. Subsequently, European ancestry studies have provided some evidence that high BMI is a causal risk factor for major depression. Ever since, it has been a matter of ongoing research to establish whether this link is due to shared metabolic mechanisms. We uncovered that the genetic correlations of depression in individuals of East Asian descent with metabolic traits were opposite to that observed for individuals of European descent, e.g. higher weight was linked to lower depression risk. The opposite direction of effect of this risk factor across populations could suggest that the link between depression and weight is social rather than metabolic in nature. This has immense implications for research into cardiovascular risk factors and depression as well as effective approaches for prevention (Giannakopoulou et al, 2021, JAMA Psychiatry).
Currently, the smallest ancestry group in AnDi are individuals of South Asian ancestry (6%). To address this, as part of DIVERGE, we established the PASCAD study, the first large study of depression genetics in Pakistan. This is an entirely new data collection and covers very detailed environmental as well as genetic information to address the immense data gap. For the next part of the programme, we will complete the collection and analyse these data to learn more about the interplay between genetic and environmental factors in causing depression.
