By Jean Wong
Content Warning: Discussion of depression and suicide.
Depression, one of the most common mental illnesses, is also called major depressive disorder (MDD) or clinical depression. This disease affects around 350 million people around the world. It’s a disease of the brain rather than the body, and causes pervasive feelings of sadness, numbness, or loss of interest in everyday activities. The disease can make someone feel hopeless, and like there is no way out of the pit that they are in. It is far more complicated to treat depression than simply cheering a person up, and it may be treated with cognitive-behavioral therapy (CBT), which aims to help patients become aware of negative thought patterns and change them. For severe depression, medication may also be used to treat it. Antidepressants can improve mood and motivation in depressed people.
MDD is a serious disease that is treated with medication and therapy, and it is different from a temporary bout of sadness. Depression also has genetic causes. It is a complex disorder, and its causes cannot simply be traced to one gene, however, there is certainly a genetic component for the risk of developing depression. In order to study depression, scientists can study twins. Identical twins share 100% of their genes, while fraternal twins share only 50%--therefore, if a disease is traceable to a genetic cause, an afflicted person’s identical twin will be more likely to have the disease than an afflicted person’s non-identical twin. Twin studies showed that heritability of depression is 40-50%, so therefore, about 50% of the causes of depression are genetic, the other 50% can be attributed to psychological or physical factors. Alternatively, in some cases depression risk may be completely genetic, and in other cases it is not genetic at all—there still isn’t enough information about the genetics of MDD to know.
The causes of depression are still somewhat unknown. Some causes include the aforementioned genetic factors, but stress, environmental conditions, childhood abuse, nutrient deficiency, and levels of hormones (such as dopamine and serotonin) can also play a role in depression. There are also epigenetic factors involved in depression, where gene regulation is changed, but nothing on the level of DNA changes. The same environmental factors that cause depression, such as psychological stress and trauma or difficult conditions, can lead to changes at the epigenetic level, like changing the rate of DNA methylation (where the methyl molecule, CH3, is added to the DNA at the 5’ position of cytosines in CpGs). Tentatively, patients with MDD were found to have hypermethylation in loci encoding brain derived neurotrophic factor, which is a molecule involved in changes in learning and memory, and SLC6A4 (the serotonin transporter gene). Regardless, these results were variable. By comparing the brains of psychiatrically healthy patients with post-mortem brains of those who had died by suicide, as well as the blood of MDD patients vs control patients, a few case-control differences in DNAm were found. There was overlap between the differentially methylated regions in the blood and brain (in Brodmann area 10). The loci with the most overlap were GABBR2, and two in RUFY3, which are genes important for regular brain function4.
Despite these developments in tracing the epigenetic causes of depression, more remains to be done. Histone modification has also been studied in depression. Differences in histone modification between depression cases and control patients have been observed, however, there are very few studies regarding histone modification. miRNAs, or small noncoding RNA strands that bind to DNA and regulate it at the epigenetic level, have also been studied in depression, such as miR-1202, which regulates GRM4, a glutamate receptor. Comparisons between healthy controls and MDD patients who died by suicide showed that miR-1202 was downregulated in patients with MDD. In addition, miR-1202 levels increased in patients after 8 weeks of treatment with antidepressants. miRNAs have the potential to be used as biomarkers in MDD, but this part of the field is unexplored, and more studies are needed4.
1) InformedHealth.org [Internet]. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006-. Treatments for depression. [Updated 2020 Jun 18]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279282/
2) Levinson, D. F., & Nichols, W. E. (n.d.). Major Depression and Genetics. Genetics of Brain Function. https://med.stanford.edu/depressiongenetics/mddandgenes.html
3) Alshaya D. S. (2022). Genetic and epigenetic factors associated with depression: An updated overview. Saudi journal of biological sciences, 29(8), 103311. https://doi.org/10.1016/j.sjbs.2022.103311
4) Penner-Goeke, S., & Binder, E. B. (2019). Epigenetics and depression. Dialogues in clinical neuroscience, 21(4), 397–405. https://doi.org/10.31887/DCNS.2019.21.4/ebinder
5) Miranda, M., Morici, J. F., Zanoni, M. B., & Bekinschtein, P. (2019). Brain-Derived Neurotrophic Factor: A Key Molecule for Memory in the Healthy and the Pathological Brain. Frontiers in cellular neuroscience, 13, 363. https://doi.org/10.3389/fncel.2019.00363