You are sitting in the psychiatrist's office, nervous about your test results. You feel depressed for a while, and your mother also had this mental condition. The psychiatrist breaks the news: ‘ I’m sorry, but you have major depressive disorder.  A few genes you carry made you susceptible, and the recent trauma you experienced, unfortunately, brought out the condition. However, in the last few decades, researchers have found effective treatment for patients with a similar genetic background to yours.’ This is how an imaginary conversation could sound in the future, and recent findings could pave the way to the personalised medicine of depression.

What is major depressive disorder?

When someone hears the word ‘depression’, the majority of people imagine a sad, maybe crying person in a dim room. But depression is not merely a bad mood that everyone experiences in their lives. Clinical depression or major depressive disorder (MDD) is a serious mental health condition that is characterised by two core symptoms: depressed mood (feeling sad, empty, and hopeless) and anhedonia (losing the feeling of pleasure and interest in activities that previously meant joy). Besides these symptoms, cognitive problems (such as trouble concentrating, thoughts of death) and physiological signs, like loss of appetite or overeating, lack of sleep or too much sleep, cause an extra burden on patients.

Depression is a chronic condition, but usually comes in episodes which can last from weeks to months. It is estimated that 8-17% of society is affected by MDD at least once in their lifetime¹. This mental illness represents the leading cause of disability worldwide, because a depressive episode limits someone’s concentration, motivation, and ability to work.²

MDD is the result of multiple interacting risk factors. . These include childhood adversity and  stressful life events in adulthood, such as serious illness or divorce. In addition to environmental circumstances,MDD also shows high heritability. Those who have a family member affected by depression are 30-50% more likely to receive the same diagnosis in their lives.^1,2,3 But how can genes affect depression?

Genes and their roles in depression

Genes are specific parts of the DNA (1-2%), the basic physical and functional units of heredity, and the sources for creating proteins in our body. Certain diseases are monogenic, such as cystic fibrosis, in which means one faulty gene is responsible for the condition. But the majority of the diseases are polygenic, like depression, which means multiple genes can play a role in its development². Critically, carrying a particular gene variant does not necessarily lead to a condition. 

Imagine that genes are ingredients of an apple pie recipe. The different types of flour, like plain flour or wholemeal flour, are variants of the same gene. Apples can be Jonagold or Pink Lady. Egg, sugar, and butter likewise have multiple options. Using the same portions but from different ingredients will lead to different apple pies. There will be delicious ones, and there will be barely edible ones. In the case of depression, this means that sometimes the disease will not show, and sometimes it will, but each person will have unique symptoms. This illustrates the concept of genetic heterogeneity. 

Unfortunately, this image is even more complex because genes are affected by environmental factors. These factors can be negative, such as stress or an unhealthy diet, and positive, like social support or regular exercise. If we follow our analogy, environmental factors are the recipe instructions. Different instructions, such as the baking time and temperature, even with the same ingredients, will lead to dissimilar apple pies.

And if you combine different instructions with different ingredients, the resulting apple pies will be even more diverse. In the case of depression, the researchers aim to find the right ingredients (genes) and instructions (environmental factors), which, in combination, can lead to this mental condition. However, this complicated image is not yet fully understood. But some results can provide directions for the genetic studies of depression.

Single genes and their effect on depression

Researchers have suggested for a long time that the biological reason for depression is the dysregulation of certain hormones and neurotransmitters, which are small proteins that serve as messengers in the communication of nerve cells. The most commonly studied neurotransmitter is serotonin. One of its regulators is called the serotonin transporter, whose gene has a specific region that is named 5-HTTLPR. Some people have a short sequence (S) in this region, while others have a long (L) version.⁴ The short version 5-HTTLPR is commonly associated with a higher risk of stress-related mental illness, such as depression and anxiety.⁵ Another neurotransmitter is the brain-derived neurotrophic factor (BDNF), which is crucial for the nerve cells' development, growth and proper functioning. The gene of BDNF has a variation called val66met, and it is often associated with increased risk for depression.⁶

However, the importance of both the serotonin transporter gene and BDNF is questionable. Comprehensive studies failed to replicate the previously mentioned results, and the importance of the 5-HTTLPR short variant⁷ and the BDNF val66met variation in depression.^8,9 Thus, researchers focused on the combined effect of these two genetic traits and environmental factors. The final results draw a different image of the roles of these genes.

Besides the 5-HTTLPR and BDNF variants, childhood adversity as an environmental risk factor was involved in a study.⁴ In this case, the highest risk to depression was the short variant of 5-HTTLPR and the BDNF val66met together. However, if they examined people who did not have a history of childhood adversity, this highest risk became the lowest, and the new riskiest genetic traits were the long variant of 5-HTTLPR combined with val66met. This highlights a crucial gene environment interaction.

Another study involved family environment and age in the analysis, and they drew an interesting conclusion.¹⁰ At the age of 15, without any risk gene, the abusive or supportive family environment had little effect on depression. The group carrying risk variants but coming from a good family environment showed fewer depressive symptoms than the participants without any risk genes. However, risk genes and a bad family background meant more depressive symptoms. In the age of early adulthood, this image had changed. People assigned male at birth showed no connection between genetic and environmental factors. But people assigned female at birth carrying risk genes and having an unsupportive family, had a high risk of developing MDD. Surprisingly, having a good family environment in the presence of the short 5-HTTLPR or val66met did not mean protection against this mental condition anymore.

These findings provide insight into what single-gene studies can discover about the background of a polygenic disease.

Multiple genes and factors behind depression 

Given the complexity of single gene interactions, there is an option to study the whole genome, which means a method to consider every gene in the DNA. A study involving 800,000 participants found more than 100 variants linked to 269 genes¹¹. These genes were mainly involved in the communication of nerve cells in the prefrontal cortex, which brain region that regulates mood and cognitive function.

As previously mentioned, genes alone do not necessarily mean the development of a disease. Another option to study the connection between genes and their effect is the transcriptome-wide study. This method focuses not on the genes, but on RNAs, the molecules that are transcribed from genes, and they are the first step in synthesising proteins. A transcriptome-wide study identified 53 risk genes in a depression study, and 7 were consistent findings¹². These genes are involved in nerve cell communication, neurotransmitter regulation, and nerve cell development. 

Another large-scale study focused on the subtypes of depression based on its multimorbidity study¹³. Multimorbidity means that a patient has more than one disease simultaneously. The researchers identified seven subgroups (or clusters) based on multimorbidity, lifestyle habits (such as body mass index or BMI) and depression onset age. Then they tried to localise gene differences in each subtype. The following table shows their findings.

Table 1. The results of a depression multimorbidity study

These studies show the diversity of depression. Some forms are more genetic, others are more influenced by lifestyle and stress. Because only half of the patients react positively to antidepressant treatment, understanding the reasons can help to develop more efficient, personalised treatment.¹⁴ Understanding this diversity is key to developing better diagnostic tools and targeted therapies. 

Summary

Major depressive disorder is a serious mental condition that causes an significant burden for patients and society. Its genetic background is still not fully understood, but the serotonin transporter and BDNF genes seem to play a crucial role. New, comprehensive study methods can map a broader range of gene variants and their relation to environmental factors. These genetic studies could open the way for personalised medicine in depression treatment.