Traumatic experience can induce lasting changes to abused children’s gene regulation that can last through adulthood, putting them at high risk of anxiety and mood disorders. Scientists at the Max Planck Institute of Psychiatry report that genetic variants of the FKBP5 gene, an important regulator of the stress hormone system, can influence epigenetic alterations in this gene induced by early trauma.
The team found that in individuals with a certain allele of FKBP5, trauma causes long-term changes in DNA methylation. 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. As a result, those affected find themselves less able to cope with stressful situations throughout their lives, frequently leading to depression, post-traumatic stress disorder, or anxiety disorders in adulthood.
Research group leader Elisabeth Binder of the Max Planck Institute of Psychiatry examined the DNA of almost 2,000 Afro-Americans who had been repeatedly and severely traumatized as adults or in childhood. One-third of trauma victims had become ill and were now suffering from post-traumatic stress disorder. The risk of developing post-traumatic stress disorder rose with increasing severity of abuse only in the carriers of a specific genetic variant in the FKBP5 gene. The scientists hoped to cast light on the mechanisms of this gene-environment interaction by comparing modifications of the DNA sequence of victims who had not become ill with that of those who had.
The scientists were then able to demonstrate that the genetic FKBP5 variant does make a physiological difference to those affected, as seen in nerve cells. Extreme stress and the associated high concentrations of stress hormones bring about an epigenetic change. A methyl group is broken off the DNA at this point, causing a marked increase in FKBP5 activity. This lasting epigenetic change is generated primarily through childhood traumatization. Consequently, no disease-related demethylation of the FKBP5 gene was detected in participants who were traumatized in adulthood only.
“Depending on genetic predisposition, childhood trauma can leave permanent epigenetic marks on the DNA,” explains Torsten Klengel, M.D., one of the study authors. “The consequence is a permanent dysregulation of the victim’s stress hormone system, which can ultimately lead to psychiatric illness. Decisive for victims of childhood abuse, however, is that the stress-induced epigenetic changes can only occur if their DNA has a specific sequence.”
The investogators say this study improves our understanding of psychiatric illnesses that arise from the interaction of environmental and genetic factors. The study was published online yesterday in Nature Neuroscience under the title “Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions”.
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