Major depressive disorder is a significant health problem, but its biological underpinnings are not well understood. That’s partly because there is variation in both the symptoms of the disease and its heritability. A recent study published in Natural genetics identified five independent gene variants from four genome regions associated with depression, raising hopes that we can better control the disorder.
The study used a meta-analysis of data collected by consumer genetics company 23andMe and previously published studies on depression. These studies can identify regions of the chromosome – and sometimes individual genes – that are often inherited along with the condition. A correlation can imply a causation.
The most significantly associated gene was OFLM4, which encodes olfactomedin-4, a protein that promotes tumor growth and cell adhesion. This gene has not previously been associated with psychiatric disorders, but it is known to be expressed in some brain regions, including the amygdala and temporal lobe.
The second most significantly associated region contained two genes associated with central nervous system disorders and dysregulation of nerve cell function. This region encodes a protein known as myocyte enhancer factor, which controls gene expression and cellular differentiation. It also contains the gene for transmembrane protein 161B, which is located on the cell membrane (otherwise we don’t know much about it).
Comparing the 23andMe dataset with a replication dataset, the authors found a total of 15 independent chromosomal regions that stood out. Many of the top associations seemed to be close to genes encoding proteins involved in gene regulation; these particular regulators generally help control the development of the central nervous system. These genes are most active in the CNS and the tissues in which they are most commonly found span different regions of the brain or parts of the nervous system, indicating that they clearly have the potential to be involved in depression.
In both datasets used, the 23andMe dataset and the comparison dataset, the authors found that people who self-reported depression were significantly more likely to have the genes associated with depression. These data indicated that most people are probably pretty good at self-assessing their depression.
Overall, the study was able to identify 17 independent locations in the genome associated with a diagnosis of major depression. However, the study failed to replicate findings from previous genome-wide association studies in Chinese populations. The authors say this discrepancy should not be surprising because these studies were conducted in populations with different demographics – this study was only conducted in people of European descent.
This divergence between the results of studies in different populations serves to highlight the heterogeneity of major depression, especially among groups of people with different genetic backgrounds – it is not a single, simple disorder.
While the study provides some insight into previously unknown associations between genes and depressive disorders, we’re only just beginning to get to grips with its genetic underpinnings. Since this disease varies in both symptoms and heritability, a more thorough characterization could help doctors develop more accurate diagnostic tools and more effective treatments to help the millions of people who suffer from the debilitating disease.
Natural genetics2016. DOI: 10.1038/ng.3623 (About DOIs).
Frame image by Michael Summers