Biasing the system: investigating factors in risk and resilience for psychiatric disease

The aim of this lecture by Professor Elizabeth Binder of the Max Planck Institute of Psychiatry, Germany was to address the molecular mechanisms that describe how early-life adversity can be embedded in and affect cellular function, and shift an individual towards risk or resilience for psychiatric disease. It is known that adversity in utero or even earlier can predispose some people to psychiatric disease, whereas some others are more resilient to this exposure. What factors may play a role in determining who develops an illness while another remains unaffected?

This increased risk for disease results from a complex interplay of genetic predisposition and environmental factors, which will vary for different individuals over time. Patients with similar symptoms of psychiatric disease may therefore have reached that point as a result of different risk trajectories. It is therefore extremely difficult, if not impossible, to work backwards from patient presentation to investigate the early-life causes of their disease. Rather it may be easier to look at candidate risk factors at the molecular level, and follow their effects longitudinally.

The glucocorticoid response provides a ‘bridge’ between environmental adversity and DNA expression2

Stress response bridges behavioral effects and DNA transcription

A good candidate for gene–environment interactions is the hormone systems that mediate environmental stress responses. The glucocorticoid system has been shown to be unbalanced in patients with psychiatric disorders.1 In addition, the glucocorticoids exert their effects at the level of DNA transcription within the cell. They therefore could provide a ‘bridge’ between environmental adversity and DNA expression.2

Genetic and epigenetic effects of glucocorticoids

The effects of glucocorticoids on genetic factors was investigated in a cellular model of human hippocampal progenitor cells. When these cells were proliferating, treatment with glucocorticoids produced large changes in gene expression that reverted when the glucocorticoid was washed out. Changes in epigenetics were also detected, with demethylation of regulatory sites, producing a lasting effect on sites associated with glucocorticoid regulation.

Early exposure to stress may produce an epigenetic ‘memory’ that increases risk from further adversity

Poised for future adversity

These changes appeared to produce what Professor Binder caller ‘poised states’. “Poised states” is, exposure to glucocorticoids resulted in epigenetic changes that, in turn, could result in greater activation of the system on subsequent exposure – and therefore, a potential vulnerability to stressful events. She linked these changes to results on human adversity from post-mortem data. Early exposure to stress and to glucocorticoids may not increase gene expression, but produce an epigenetic ‘memory’ that is then unmasked at later insults and raises the cellular response to stress. This provides a model for risk and resilience to psychiatric disorders.

Genetic mediation of risk and resilience

Early stress and an increased cortisol response could set people on a risk trajectory for later psychiatric disorders, and that this process may be mediated in part by genetic and epigenetic effects

How do genetic factors moderate this pathway, and therefore provide risk or resilience? The gene FKBP5 is upregulated in limbic and other areas by glucocorticoid exposure, and it seems to signal an immediate response to stress. Its activation also provides negative feedback on glucocorticoid production to moderate the stress response, and interacts with many other metabolic pathways that affect neuronal functioning. FKBP5 is therefore a good candidate as a mediator between the stress response and future vulnerability.

Exposure to trauma produces demethylation of sites on FKBP5,3 some of which overlap with the sites demethylated by glucocorticoid treatment. These demethylation changes revert after 24 hours in healthy volunteers, but the dynamics are different for patients with psychiatric disorders. In patients, with PTSD, this demethylation of FKBP5 following stress has been shown to be much more stable over time. The reasons for this are currently being investigated.

Early results indicate a trajectory of psychosocial problems after early adversity combined with genetic risk

The longitudinal effects of FKBP5 demethylation and disinhibition are also starting to be investigated. In the Family life partner study, children exposed to violence at home were investigated for their FKBP5 genotype, alleles of this gene associated with greater risk, and their response to a cortisol challenge at a young age. Those with more risk alleles showed a slower return to baseline in their cortisol response, and this effect was exacerbated by having experienced interpersonal violence at home. As the children grew older, this risk profile was associated with greater emotional reactivity, lower levels of executive function, and lower reading ability at school. These may all predispose a person to later development of psychiatric problems. The relationship between FKBP5 disinhibition, exposure to violence at an early stage and these emotional and behavioral problems at a later stage was not deterministic – there are many other complex factors that might intervene in this process. However, it did appear that early stress and an increased cortisol response could set people on a risk trajectory for later psychiatric disorders, and that this process may be mediated in part by genetic and epigenetic effects. Future research will be focused on what moderates that trajectory, and what interventions may be possible to prevent this. 

For a complementary report on psychosocial risk factors in schizophrenia, see


  1. Pariante CM, Lightman SL. Trends Neurosci. 2008;31:464–8.
  2. Vaiserman AM, Koliada AK. Hum Genomics. 2017;11(1):34.
  3. Zannas AS, et al. Neuropsychopharmacology. 2016;41(1):261-74.