Stress susceptibility: genetic and environmental influences on brain function and gene expression in blood following stress
Stress is a risk factor for anxiety disorders, but not all individuals exposed to stress develop anxiety. Differences in stress susceptibility can be explained by genetic and environmental factors rendering some individuals more prone to develop anxiety following stress than others. Stress influences anxiety via its effect on the brain. To understand why some individuals are more vulnerable to stress, we need to understand genetic and environmental influences on stress-related brain function. Our first aim is to determine genetic and environmental effects on brain function during stress. Stress also affects the immune system, which in turn could have long-term effects on brain function. Genes expressed by immune cells could produce compounds that affect brain function long after stress. Hence, stress susceptibility could depend on how genes and environment modulate stress induced gene-expression. Our second aim is to determine genetic and environmental influences of stress on gene expression in blood. Because we want to know how stress influences anxiety, our third aim is to establish which brain systems and gene transcripts are associated with elevated subjective ratings of anxiety during stress. Results will be important for uncovering novel pathways that could explain how stress causes anxiety in some individuals but not in others.
Final report
Project aims
The objective of the research project was to investigate how genetic factors contribute to stress related responses in the brain and blood. This could help us understand why some individuals are more prone to develop anxiety or depression following stress. Our first aim was therefore to determine the heritability of both anxiety and depression on their own, as well when they occur together, using register data from the Swedish Twin Registry. Our next aim was to determine which genes change their activity in blood following stress, allowing us to then estimate genetic influences on stress related gene expression. We were also interested in understanding to what extent stress related brain function is heritable. To this end, we recruited identical and fraternal twins from the Swedish Twin Registry, who performed a standardized social stress test while blood was collected and stress related tasks while brain activity was recorded. By comparing similarity in stress measures between identical twins, sharing 100% of their genetic material, and fraternal twins, sharing 50% of their genetic material, we can estimate to what extent individual variation in gene expression and brain activity can be attributed to genetic versus environmental factors. In total, 302 twins participated in the stress test, 279 of which also performed a stress related task in an MRI-scanner that recorded brain activity. To our knowledge, this is the largest study to date that has used RNA-sequencing (RNA-seq) to study stress related gene expression across the whole genome.
Implementation of the project
Participants were invited to Studieenheten Akademiskt Specialistcentrum at Sabbatsberg hospital in Stockholm. Blood samples were collected by research nurses at baseline (before stress), and 4 times following the Trier Social Stress test. Functional MRI data was collected as an index of brain activity at Stockholm University Brain Imaging Center on a separate occasion.
Heritability of anxiety disorders
We first aimed at determining the heritability of anxiety and depression. In a sample consisting of 12558 twins, we found that depression and anxiety were moderately heritable, in line with previous studies. However, comorbid anxiety and depression was considerably more heritable than either condition on its own (Tabrizi et al., 2025), a novel result. This indicates that genetic variation contributes substantially to individual variation in comorbid anxiety and depression.
Heritability of stress responses
The blood level of cortisol, a hormone released following activation of the hypothalamic-pituitary-adrenal axis, increased following stress as expected, and the concentrations were moderately heritable (56-64%). The Neutrophil-to-Lymphocyte-Ratio (NLR), a marker of inflammation, was less heritable (22-35%) than cortisol. NLR slowly increased following stress, peaking at 90 minutes post stress. An important result was that cortisol levels during stress were correlated with NLR 90 minutes later (Grönvall et al., 2025), suggesting that cortisol levels could drive this marker of inflammation following stress.
Somewhat surprisingly, there was a rapid change in gene expression following stress in more than 3000 genes of the roughly 23 000 whose counts were measured across the whole transcriptome through RNA-seq. Previous studies are scarce and have generally been too small to have adequate statistical power to identify such large numbers of differentially expressed genes. Further, they have not measured gene expression immediately following stress because of the assumption that gene expression changes are delayed 30-60 minutes. Our results suggest that the change in gene expression in blood occurs immediately following stress and could therefore be mediated by sympathetic nervous system (SNS) activation, or other fast acting peripherals nervous system stress responses. This assumption was partially supported by our findings of stress related changes in expression of the cAMP response element-binding (CREB) transcript which is activated by noradrenergic activation of immune cells by the SNS. A gene ontology (GO) analysis of the differentially expressed genes indicated biological processes involved in immunity (Natural killer cells, B-cells, T-cells, chemokines, cytokines), cell adhesion and cell structure.
The heritability of gene expression at baseline (before stress) was in general higher than stress-induced change in gene expression. This indicates that genetic factors are important for individual differences in baseline gene expression, whereas environmental factors may be more important for explaining changes in gene expression after stress. Results underscore that measuring gene expression at baseline gives limited information about genetic influences on stress induced gene expression changes. However, genes whose stress-induced change showed high heritability also showed high heritability at baseline. Combining these results therefore points to potentially heritable markers of stress that could be measured at baseline. The next question is whether gene expression can explain differences in subjective anxiety during stress between different people.
Gene expression correlates with subjective anxiety
An important result from our study is that genes involved in signal transduction, transcription regulation, stress response and immune response or inflammation showed differences in expression that were related to individual differences in subjective anxiety both at baseline and immediately following stress. Because the experience of anxiety is mediated by the brain and we here measured gene expression in peripheral blood, we speculate that: neural mediation of anxiety is manifested at the level of gene expression in blood cells or similar gene expression changes occur in brain cells that we observed in blood or that some compounds produced in the blood travels into the brain and changes functions related to anxiety. Mechanisms aside, the next step would be to understand if these gene expression markers change as people become less anxious after psychotherapy or drug therapy. If this is the case, the expression of these genes could serve as much needed prognostic markers of treatment response. So far, we found that the heritability of some of the genes whose expression correlated with experienced anxiety is moderate (h2 range 0.4-0.6). This could indicate that genetic factors influencing the activity of these genes following stress may predispose some individuals to be more vulnerable to social stress than others. Uncovering the mechanisms behind these genetic influences on gene expression could generate new ideas for targets for treatment of stress related disorders.
Genetic influences on stress related brain function
We performed an fMRI-study of learned fear in twins to understand the extent of genetic influences on brain function. We found moderate genetic influences on brain function supporting fear conditioning when participants learned that a character was dangerous and predicted an electric shock (Kastrati et al., 2022). This shows that our genetic background partly shapes the functional brain activation patterns that allow us to learn from stressful experiences. This in turn may be relevant for understanding individual differences in risk for developing stress related disorders. To understand more about the neurotransmitters involved in fear conditioning, we performed a combined positron emission tomography (PET) and fMRI study (Frick et al., 2022). In this study we found that dopamine release in the striatum and the amygdala occurred during fear learning, supporting the role of dopamine in stressful experiences. We further showed that brain responses during fear conditioning were correlated with bodily arousal (Vinberg et al., 2022).
In addition to learned fear, there are many types of feared situations that do not necessitate learning. One such innate stressor is infringement on personal space. We discovered genetic influences on brain networks monitoring interpersonal distance in the occipital and parietal cortices (Rosén et al., 2022). These functional networks were separate from the networks that supported fear conditioning (Kastrati et al., 2022), showing that genetic influences are specific to activations of task relevant brain areas.
Conclusion
In summary, we have shown that 1) gene expression at baseline is more heritable than stress induced gene expression. 2) stress induced gene expression correlates with experienced anxiety during stress, and 3) stress related brain activation patterns are heritable. These results inform on vulnerability factors for stress and can give clues to new markers for stress, anxiety and depression.
Open access
All publications from the project are open access.
The objective of the research project was to investigate how genetic factors contribute to stress related responses in the brain and blood. This could help us understand why some individuals are more prone to develop anxiety or depression following stress. Our first aim was therefore to determine the heritability of both anxiety and depression on their own, as well when they occur together, using register data from the Swedish Twin Registry. Our next aim was to determine which genes change their activity in blood following stress, allowing us to then estimate genetic influences on stress related gene expression. We were also interested in understanding to what extent stress related brain function is heritable. To this end, we recruited identical and fraternal twins from the Swedish Twin Registry, who performed a standardized social stress test while blood was collected and stress related tasks while brain activity was recorded. By comparing similarity in stress measures between identical twins, sharing 100% of their genetic material, and fraternal twins, sharing 50% of their genetic material, we can estimate to what extent individual variation in gene expression and brain activity can be attributed to genetic versus environmental factors. In total, 302 twins participated in the stress test, 279 of which also performed a stress related task in an MRI-scanner that recorded brain activity. To our knowledge, this is the largest study to date that has used RNA-sequencing (RNA-seq) to study stress related gene expression across the whole genome.
Implementation of the project
Participants were invited to Studieenheten Akademiskt Specialistcentrum at Sabbatsberg hospital in Stockholm. Blood samples were collected by research nurses at baseline (before stress), and 4 times following the Trier Social Stress test. Functional MRI data was collected as an index of brain activity at Stockholm University Brain Imaging Center on a separate occasion.
Heritability of anxiety disorders
We first aimed at determining the heritability of anxiety and depression. In a sample consisting of 12558 twins, we found that depression and anxiety were moderately heritable, in line with previous studies. However, comorbid anxiety and depression was considerably more heritable than either condition on its own (Tabrizi et al., 2025), a novel result. This indicates that genetic variation contributes substantially to individual variation in comorbid anxiety and depression.
Heritability of stress responses
The blood level of cortisol, a hormone released following activation of the hypothalamic-pituitary-adrenal axis, increased following stress as expected, and the concentrations were moderately heritable (56-64%). The Neutrophil-to-Lymphocyte-Ratio (NLR), a marker of inflammation, was less heritable (22-35%) than cortisol. NLR slowly increased following stress, peaking at 90 minutes post stress. An important result was that cortisol levels during stress were correlated with NLR 90 minutes later (Grönvall et al., 2025), suggesting that cortisol levels could drive this marker of inflammation following stress.
Somewhat surprisingly, there was a rapid change in gene expression following stress in more than 3000 genes of the roughly 23 000 whose counts were measured across the whole transcriptome through RNA-seq. Previous studies are scarce and have generally been too small to have adequate statistical power to identify such large numbers of differentially expressed genes. Further, they have not measured gene expression immediately following stress because of the assumption that gene expression changes are delayed 30-60 minutes. Our results suggest that the change in gene expression in blood occurs immediately following stress and could therefore be mediated by sympathetic nervous system (SNS) activation, or other fast acting peripherals nervous system stress responses. This assumption was partially supported by our findings of stress related changes in expression of the cAMP response element-binding (CREB) transcript which is activated by noradrenergic activation of immune cells by the SNS. A gene ontology (GO) analysis of the differentially expressed genes indicated biological processes involved in immunity (Natural killer cells, B-cells, T-cells, chemokines, cytokines), cell adhesion and cell structure.
The heritability of gene expression at baseline (before stress) was in general higher than stress-induced change in gene expression. This indicates that genetic factors are important for individual differences in baseline gene expression, whereas environmental factors may be more important for explaining changes in gene expression after stress. Results underscore that measuring gene expression at baseline gives limited information about genetic influences on stress induced gene expression changes. However, genes whose stress-induced change showed high heritability also showed high heritability at baseline. Combining these results therefore points to potentially heritable markers of stress that could be measured at baseline. The next question is whether gene expression can explain differences in subjective anxiety during stress between different people.
Gene expression correlates with subjective anxiety
An important result from our study is that genes involved in signal transduction, transcription regulation, stress response and immune response or inflammation showed differences in expression that were related to individual differences in subjective anxiety both at baseline and immediately following stress. Because the experience of anxiety is mediated by the brain and we here measured gene expression in peripheral blood, we speculate that: neural mediation of anxiety is manifested at the level of gene expression in blood cells or similar gene expression changes occur in brain cells that we observed in blood or that some compounds produced in the blood travels into the brain and changes functions related to anxiety. Mechanisms aside, the next step would be to understand if these gene expression markers change as people become less anxious after psychotherapy or drug therapy. If this is the case, the expression of these genes could serve as much needed prognostic markers of treatment response. So far, we found that the heritability of some of the genes whose expression correlated with experienced anxiety is moderate (h2 range 0.4-0.6). This could indicate that genetic factors influencing the activity of these genes following stress may predispose some individuals to be more vulnerable to social stress than others. Uncovering the mechanisms behind these genetic influences on gene expression could generate new ideas for targets for treatment of stress related disorders.
Genetic influences on stress related brain function
We performed an fMRI-study of learned fear in twins to understand the extent of genetic influences on brain function. We found moderate genetic influences on brain function supporting fear conditioning when participants learned that a character was dangerous and predicted an electric shock (Kastrati et al., 2022). This shows that our genetic background partly shapes the functional brain activation patterns that allow us to learn from stressful experiences. This in turn may be relevant for understanding individual differences in risk for developing stress related disorders. To understand more about the neurotransmitters involved in fear conditioning, we performed a combined positron emission tomography (PET) and fMRI study (Frick et al., 2022). In this study we found that dopamine release in the striatum and the amygdala occurred during fear learning, supporting the role of dopamine in stressful experiences. We further showed that brain responses during fear conditioning were correlated with bodily arousal (Vinberg et al., 2022).
In addition to learned fear, there are many types of feared situations that do not necessitate learning. One such innate stressor is infringement on personal space. We discovered genetic influences on brain networks monitoring interpersonal distance in the occipital and parietal cortices (Rosén et al., 2022). These functional networks were separate from the networks that supported fear conditioning (Kastrati et al., 2022), showing that genetic influences are specific to activations of task relevant brain areas.
Conclusion
In summary, we have shown that 1) gene expression at baseline is more heritable than stress induced gene expression. 2) stress induced gene expression correlates with experienced anxiety during stress, and 3) stress related brain activation patterns are heritable. These results inform on vulnerability factors for stress and can give clues to new markers for stress, anxiety and depression.
Open access
All publications from the project are open access.