General Health

Exploring the link between genes and major depressive disorder

A mental disorder is identified with a strong clinical presentation of any kind of behavioural, psychological or biological dysfunction an individual experiences. Mental disorders present themselves in either of the two opposite manners: 

  1. Mania:  where individuals intensely display unrealistic feelings of excitement and euphoria.
  2. Depression: where individuals feel sad and dejected most of the day but may have a normal mood from time to time.

According to the WHO, more than 264 million people of all ages suffer from depression and the rates were seen at an all-time high during the COVID-19 pandemic, due to reduced interactions with other individuals and spending more time at home.

Clinical Depression, also known as Major Depressive Disorder, is the most common form of depression. An individual who suffers from major depression experiences a loss of interest in pleasurable activities and depressive moods for at least two or more weeks. The heritability of major depression is around 37% and is three times higher if a first-degree family member is suffering from depression. 

Researchers have explored a possible relationship between genes and major depressive disorder. They estimate that almost 40% of depression has genetic links and the remaining 60% can be linked to environmental factors. A deeper understanding of the etiology of depression by exploring both the genetic and the environmental determinants and the interplay between them (e.g., gene-environment interaction) will prove helpful in formulating better treatments and preventing the occurrence of depression. 

Several neurotrophic chemicals such as brain-derived neurotrophic factor (BDNF) and 5-hydroxytryptamine (5-HT) popularly known as serotonin play a huge role in neuronal function. Any kind of mutation or change in the genes that code for these chemicals can negatively impact neuronal function and cause depression. The levels of BDNF reduces as a result of social defeat and stress. Lower levels of this chemical in the hippocampus can lead to cognitive dysfunction and depressive symptoms, which can be reverted by antidepressants. From the experiments on animal models, BDNF has emerged as a modulator of the brain reward system, and absence or ectopic presence causes depressive symptoms, cognitive dysfunctions, low energy and memory deficits. 

Serotonin is produced in the brain stem region which innervates the cortical brain regions and regulates behaviour, cognition and mood. There are 15 genes that code for serotonin receptors in the mammalian brain. Research shows that the longer the duration of serotonin present in the space between neurons (synaptic cleft) the longer is the activation, leading to depression. Any kind of mutation in the genes that code for the serotonin receptors leads to abnormal serotonin signalling and is implicated with anxiety, depression and aggression-related personality traits including suicides. Unipolar depression is associated with diminished serotonergic function which leads to warping in emotion and cognitive processing. 

Antidepressants normally work in two ways – (i) prevent the reuptake of serotonin, (ii) block degradation of serotonin by inhibiting monoamine oxidase. Serotonin reuptake inhibiting drugs (SRIs) are used for the treatment of depression and anxiety with several weeks of observation. Thus, over a period of time, the amount of serotonin increases and they help in improving mood and reduce anxiety. Increased gene activity of BDNF led to a concomitant increase of the chemical in the hippocampus and cortex region of rodent brains following antidepressant treatment.

Some of the established environmental risk factors for depression include poverty, negative family relationships and parental divorce, child maltreatment, loss of a family member and other stressful life events more generally. While the risk of depression is elevated in the immediate aftermath of experiencing these environmental adversities, the effects of adversity can persist over the life course.

The genetics of depression and stress is less explored even though a significant proportion of the population are sufferers. Since many of the sufferers are unable to openly state their struggles with depression, a small sample size serves as a limitation for such studies. With the advent of sophisticated technologies, many research groups have shifted their research from candidate gene approach, to whole-genome analysis approach like genomewide association studies and next-generation sequencing. An early understanding of an individual’s genetic trait to mood disorders may help design better management strategies that may help alleviate the risk of the disorder. 

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