Major depressive disorder is a significant health problem, but its biological underpinnings aren't well understood. That's in part because there’s variability in both the disease's symptoms and its heritability. A recent study published in Nature Genetics identified five independent gene variants from four genome regions that are associated with depression, raising hopes that we can get a better handle on the disorder.

The study used a meta analysis of data collected by consumer genetics company 23andMe as well as previously published studies of depression. These studies can identify regions of the chromosome—and sometimes individual genes—that are frequently inherited along with the disorder. A correlation can imply causation.

GWAS and 23andMe Genome-wide association studies examine genetic variants spread throughout the genome, looking for ones that appear to be associated with a health outcome or disease. These variants aren't necessarily mechanistically linked to the disease, and they don't necessarily code for proteins that cause the disease; they're simply more common in people who have the disease. Further studies are needed to determine whether this association is an indication of something significant. Genome-wide association studies examine genetic variants spread throughout the genome, looking for ones that appear to be associated with a health outcome or disease. These variants aren't necessarily mechanistically linked to the disease, and they don't necessarily code for proteins that cause the disease; they're simply more common in people who have the disease. Further studies are needed to determine whether this association is an indication of something significant. 23andMe is a private company that genotypes samples sent in by interested consumers. When people elect to use the service, they have the optional choice to participate in the various government and academic research partnerships that 23andMe engages in. The data for the 23andMe data set included in this study comes from a population of these voluntary participants.

The most significantly associated gene was OFLM4, which encodes for olfactomedin-4, a protein that promotes tumor growth and cell adhesion. This gene has not been previously associated with any psychiatric disorders, but it is known to be expressed in some brain regions, including the amygdala and the temporal lobe.

The second most significantly associated region contained two genes that are 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 resides on the cell membrane (otherwise, we don't know much about it).

When comparing the 23andMe data set to a replication data set, the authors found a total of 15 independent chromosomal regions that stood out. Many of the top associations appeared to be near genes encoding proteins involved in gene regulation; these specific regulators generally help control the development of the central nervous system. These genes are most active in the CNS, and the tissues they were most often found in include different brain regions or parts of the nervous system, which indicates that they clearly have the potential to be involved in depression.

In both data sets that were used, the 23andMe data set and the comparison data set, the authors saw that people who self-reported depression were considerably more likely to have the genes that were linked with depression. This 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 that are 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 that this discrepancy shouldn’t be surprising, because these studies were in populations with different demographics—this one was conducted only in people of European descent.

This divergence between the results of studies in different populations serves to highlight the heterogeneity of major depression, particularly among groups of people with different genetic backgrounds—it’s not a single, simple disorder.

Though the study provides some insight into previously unknown associations between genes and major depressive disorders, we're only just starting to come to grips with its genetic underpinnings. Since this disease varies in both its symptoms and heritability, a more thorough characterization could help doctors to develop more precise diagnostic tools and more effective treatments to help the millions of people who suffer from the debilitating illness.

Nature Genetics, 2016. DOI: 10.1038/ng.3623 (About DOIs).

Listing image by Michael Summers