Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions

Abstract

Although the fact that genetic predisposition and environmental exposures interact to shape development and function of the human brain and, ultimately, the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not yet been elucidated. We found that a functional polymorphism altering chromatin interaction between the transcription start site and long-range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, 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. This identification of molecular mechanisms of genotype-directed long-term environmental reactivity will be useful for designing more effective treatment strategies for stress-related disorders.

Hpa Axis Related Genes and Response to Psychological Therapies: Genetics and Epigenetics

“…As all SNPs showed a low frequency of the homozygous risk allele genotype, polymorphisms were coded to reflect a dominant model, with homozygotes of the “non‐risk” allele versus “risk” allele carriers. This is in accordance with previous studies of response to environmental stimuli and psychiatric outcomes 32, 41 and interactions between genotype and DNA methylation 11…”

“…Fourth, information on exposure to trauma prior to treatment was not available for this sample. Traumatic experiences in childhood have been demonstrated to have lasting effects on DNA methylation of both the FKBP5 and GR genes 11, 12, 14, 15, 16, 17. Therefore, we are unable to make any conclusions regarding other environmental factors that may have influenced baseline DNA methylation and subsequent changes in DNA methylation during active treatment.…”

“…Our second hypothesis was that there would be an association between FKBP5 and GR methylation and response to CBT, looking at prediction by pretreatment DNA methylation, and change in DNA methylation during treatment. Previous research has demonstrated that DNA methylation patterns are linked to DNA sequence variation at a large number of locations across the genome,34, 35 and allele‐specific DNA methylation has also been reported at in FKBP5 11. Therefore, our third hypothesis was that there would be an interaction between FKBP5 and GR genotypes and DNA methylation on CBT response.…”

“…Recent molecular research has suggested that genotype‐dependent structural differences in FKBP5 may give rise to differential epigenetic changes following early‐life stress11 and subsequently functional alterations in the responsiveness of FKBP5 to glucocorticoid receptor activation 11. Epigenetic modifications of the glucocorticoid receptor gene ( NR3C1 , referred to here as GR ) have also been associated with early‐life experiences in both rats and humans.…”

Evaluating web-based cognitive-affective remediation in recent trauma survivors: study rationale and protocol

“…Specifically, early life trauma is associated with impairment in cognitive and emotional functions (Burri, Maercker, Krammer, & Simmen-Janevska, 2013; Pechtel & Pizzagalli, 2011) across studies exploring genetic (Klengel et al, 2013), psychosocial (Ogle, Rubin, & Siegler, 2013), and gene by environmental contributions (Binder et al, 2008). Early life trauma was not evaluated in this work, thereby limiting our ability to address a potential source of cognitive impairment.…”