Why do we react differently to stress

We humans react to stress both physically and psychologically, but not everyone is equally sensitive. While some people deal well with the consequences of stress, others suffer from it severely or even become ill. A new study shows that there may be some genetic variants that make some people more sensitive to stress. Accordingly, these stress-regulating genes also influence the risk of developing a psychiatric disorder. This can improve the prevention of depression and the like.

Our daily lives can be very stressful and can throw us off track at times. Some people even develop the disease during traumatic experiences or when stress persists for a long time. Whether or not we develop depression or another psychological disorder depends not only on our stress level, but also on our genes, previous studies suggest. But what genes specifically are responsible for some people’s ability to cope well with stress and stressful life events, while others develop psychological distress in response to stress?

A research group led by Signe Benner Goeke of the Max Planck Institute for Psychiatry (MPI) in Munich has addressed this question at the molecular level. To do this, the scientists used two human cell lines that are suitable as models of genetic and molecular stress response, and exposed them to the synthetic active ingredient dexamethasone, which mimics the effect of the natural stress hormone cortisol. They then used molecular genetic and statistical approaches to study genetic variants that may be linked to the cellular response to stress. To do this, Benner Goeke and her colleagues analyzed a total of 3,662 individual mutations within genetic variants in 320 genetic regions that occur most often in patients with psychiatric disorders.

People with a lot of “stress genes” also react more to stress

The analyzes showed that 547 of the genetic variants examined were involved in the hormone-induced stress response in cells. This type of stress-sensitive genetic variant occurred in approximately half of all gene regions examined. These variants are frequently found at regulatory sites in DNA, including sites that regulate neurons in the brain, the researchers reported. Benner-Goecke and her colleagues concluded that some variables may influence the risk of developing a psychiatric disorder. “We found a number of variants associated with psychiatric disorders,” says Benner-Goecke.

In other experiments, researchers examined whether the risk of developing mental illness changes when such genetic variants are present in combination. To do this, they subjected 183 and 171 test subjects to two different stress tasks, measuring hormone levels in their saliva and their eyelash reflex. In the first test, participants were asked to solve a math problem, and in the second test, they were afraid. Scientists also sequenced the DNA of test subjects to identify genetic variants present in their genome. These experiments showed that people with a greater number of stress-related genetic variants had greater amounts of the stress hormone cortisol in their saliva during and shortly after the experiences, and also had a more intense reaction to fear. Penner-Goecke and her colleagues concluded that these genetic variants influenced how violently people reacted to stressful situations.

Better prevention and treatment of mental illness is possible

“Our genes have an influence on our sensitivity to the consequences of stress,” says senior author Elizabeth Binder of MPI, summarizing the findings. This molecular mechanism could explain why stressful life events cause psychological disorders in only some people. Therefore, in addition to individual experiences and living conditions, genes also play a role. Further studies with other cell lines and more genetic loci are still needed to clarify whether researchers have already discovered all the relevant genetic variants and how they lead to the cellular stress response. However, the results can now be used to roughly predict which people are most at risk of developing a stress-related psychological disorder. Researchers say this knowledge can also be used to better prevent and treat mental disorders.

Source: Signe Benner-Goecke (Max Planck Institute for Psychiatry) et al., PNAS, doi: 10.1073/pnas.2305773120

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