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Gene x environment interactions in affective disorders - elucidating molecular mechanisms

Final Report Summary - GXE-MOLMECH (Gene x environment interactions in affective disorders - elucidating molecular mechanisms)

Epidemiological studies indicate a combined contribution of genetic and environmental factors in the risk for disease including in the form of gene by environment interactions (GxE). In particular, adverse life events, ranging in their occurrence from pregnancy to adulthood, have been identified as major risk factors for a number of psychiatric disorders and their long term impact is likely moderated by genetic factors. This ERC grant aimed at elucidating the mechanisms by which the interplay of genetic and environmental factors shapes risk and resilience to disease to help to better understand the biology of psychiatric disorders and develop novel prevention and treatment approaches. Using an array of methods in human cohorts, animals and cell culture, we could show that one putative biological mechanism implicates the ability of glucocorticoids (GC), released in response to stress, to trigger a cascade of adaptive transcriptional and epigenetic processes through glucocorticoid receptor (GR) activation. Genetic variants moderating the immediate molecular stress response also moderate the long term risk for stress and trauma-related psychiatric disorders. This now allow to identify a subset of genetic and epigenetic variable that could serve as identifiers of individuals at high risk to suffer from stress-related psychiatric disorders.

Our data also strongly implicate genetically moderated 3D chromatin conformation changes as important contributor for these gene x environment interactions. We have shown that this mechanism not only relates to FKBP5, a gene central to the stress response, but to a number of other loci, suggesting that risk and resilience to stress-related psychiatric disorders is moderated by a network of stress-sensitive transcript. Interventions targeting either FKBP5 or central nodes of this stress-response network could be promising new drug target. For FKBP5, a proof of concept study developed from this grant, investigated small molecule antagonists as potential antidepressant drugs, with first promising results in animal studies.

Overall, this ERC grant delineates a path from a molecular understanding of gene x environment interactions to biomarkers of risk and resilience and potential new drug targets in psychiatry.