Molecular mechanisms underpin gene/environment interaction

Adverse events such as abuse in childhood are closely related to risk of psychiatric disorder in adulthood. But the effects of such experiences are modulated by genetic factors. Can we begin to understand the daunting complexity of this interaction by looking at the stress hormone system, which is often dysregulated in psychiatric disorders?

The glucocorticoid receptor is a nuclear receptor which engenders a transcriptome-wide stress response in the cell. It is now clear that exposure to the stress hormone also remodels the epigenetic landscape, mostly through a decrease in DNA methylation.

Such changes, which (among other possible effects) had implications for neuronal differentiation were evident even after a washout period of twenty days. Effects were long lasting and seem capable of altering the impact of subsequent adverse stress-related events over a lifetime.

Basic molecular mechanisms are a good place to start when trying to understand complex gene-environment interactions

SNPs interact with early trauma to predict mood and anxiety disorders

Such insights prompted work on multipotent human hippocampal progenitor cells. These cells react to glucocorticoids and so may represent a good model of early exposure to stress. In this model, exposure to dexamethasone produced the expected epigenetic changes in DNA methylation.

Importantly, these changes were found to be located in gene enhancer regions that are relevant both to brain development and to risk of mood disorders. Demethylation seems to prime genes to be more reactive to future stress.

But genetic variation modulates the epigenetic response to glucocorticoid activation and to changes in transcription. And it is revealing that SNPs linked by genome-wide association studies to increased risk of schizophrenia and depression are found in the loci showing methylation changes. This association may show – at a molecular level – how the risk of stress-related disorders is determined by both environmental and genetic factors.

There are certainly many non-glucocorticoid mechanisms that influence an individual’s vulnerability or resilience to mental health problems, Professor Binder concluded. But glucocorticoids do seem able to prime an organism to respond differently to stress.