In some people, childhood trauma can interact with genotype to increase the risk of stress-related disorders such as depression or post-traumatic stress disorder (PTSD) in adulthood, but the molecular mechanisms remain unclear. The authors of this paper report that polymorphisms in the FK506 binding protein 5 (FKBP5) gene interact with early trauma to produce long-lasting epigenetic changes that increase the risk for such conditions.
FKBP5 forms part of a negative-feedback loop that regulates glucocorticoid receptor activity, and so may perturb the stress response system, leaving people vulnerable to stress-related disorders such as PTSD.
A functional polymorphism altering chromatin interaction between the transcription start site and long-range enhancers in the FKBP5 gene, increased the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements of FKBP5.
This demethylation was linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global effect on the function of immune cells and brain areas associated with stress regulation. The authors feel that these molecular pathways may be useful for future therapeutic strategies.
Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Pariante CM, Pace TW, Mercer KB, Mayberg HS, Bradley B, Nemeroff CB, Holsboer F, Heim CM, Ressler KJ, Rein T, Binder EB: Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nature Neuroscience 16(1): 33-41 (2013).
