In a global investigation headed by UCL academics, almost 200 genes associated with depression were found to be novel candidates.
The first large-scale global study of the genetics of major depression in participants of diverse ancestry groups 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. The research was published in Nature Genetics.
One of the discovered genes produces a protein that is targeted by a popular diabetic medication, demonstrating the possibility for drug repurposing. The study also identifies novel targets for possible depression treatment medications.
Although depression is highly frequent, little is still known about how it starts. Big data-driven genetic research is opening up new ways to study the illness and has identified dozens of genes linked to depression, each of which carries a very slight increased risk. It can also aid in the discovery of novel therapeutic targets; however, research to far has primarily involved individuals with European ancestry, which the researchers argue is a significant limitation, particularly for a disorder as complicated as depression.
The new work included a variety of genetic research techniques, such as transcriptome-wide association studies, genome-wide association studies, and meta-analyses of previously released data. An international research team consisting of over one million study participants of African, East Asian, South Asian, and Hispanic/Latin American descent—88,316 of whom had serious depression—reviewed genetic data from 21 study cohorts spanning multiple nations.
The study highlights several genes with possible consequences for medication development, such as NDUFAF3, and has made significant strides in identifying genes associated with depression risk, both for newly discovered associations and by supporting previous findings. The primary treatment for type 2 diabetes, metformin, targets the protein that NDUFAF3 encodes, which has been linked to mood instability in the past. This current finding implies that further investigation into metformin and depression may be necessary, as animal studies have revealed a probable association with reduced anxiety and depression.
Some genes found in the study, such as those encoding a kind of protein previously connected to a number of neurological diseases and a gene linked to a neurotransmitter involved in goal-directed behavior, may have biologically reasonable associations with depression.
A new method the research team developed to determine the degree to which a genetic association found in one ancestry group is applicable to another ancestry group, revealed that the genetic hits for depression showed less overlap across ancestry groups than expected, at about 30%. This is less overlap than previously found for other traits and diseases. Studying depression in a variety of groups is therefore even more crucial because some of the results may be ancestry-specific.
Along with Dr. Xiangrui Meng, PhD candidate Georgina Navoly, and Dr. Olga Giannakopoulou, Professor Kuchenbaecker oversaw the study. Collaborative consortia involved in the research included the Genes and Health Research Team, the 23andMe Research Team, the Psychiatric Genomics Consortium-Major Depressive Disorder Working Group, and the China Kadoorie Biobank Collaborative Group.
According to Professor Kuchenbaecker: “This is a first stage discovery effort, so more work will be needed to confirm these new targets, but finding them in the first place has been a huge and vital challenge, especially for a disorder where new medications are so urgently needed.”