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

By T. Klengel, D. Mehta, C. Anacker, M. Rex-Haffner, Jens C. Pruessner, C. Pariante, Thaddeus W. W. Pace, Kristina B. Mercer, Helen S. Mayberg, B. Bradley and 6 more. Nature Neuroscience, 2012

1,357 citations recorded by the source corpus.

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.

Subfields: Behavioral Neuroscience, Biological Psychiatry, Education

View Paper: https://www.semanticscholar.org/paper/e06cbe56f76feba1845d97c16e7c7d367f26f281

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Behavioral Neuroscience

In Biological Psychiatry

In Education

C. Nemeroff

Citations in the corpus

Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation. (2016, methodology): “FKBP5 single nucleotide polymorphisms have additionally been shown to interact with early trauma to predict both PTSD and major depression (36,37), possibly through involvement of allelespecific, environmentally dependent changes in methylation of specific cytosine-phosphate-guanine (CpG) sites (38)”
Paradise Lost: The Neurobiological and Clinical Consequences of Child Abuse and Neglect. (2016, background): “From Klengel et al. (2013).”
Effects of the social environment and stress on glucocorticoid receptor gene methylation: a systematic review (2014, neutral): “Childhood maltreatment produces an FKBP5 genotype-specific demethylation of a distal enhancer, resulting in increased FKBP5 expression, and decreased GR signalling (100).”
DNA methylation and healthy human aging (2015, background): “environmental influences, such as abuse or adversities in childhood, have also been linked to stable DNA methylation differences that persist into adulthood (Meaney, 2010; Essex et al., 2011; Borghol et al., 2012; Lam et al., 2012; Klengel et al., 2013).”
Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017, background): “…as exposure to childhood trauma is associated with epigenetic de-methylation near the rs1360780 FKBP5-SNP that is associated with GR dysregulation and increased expression of mRNA transcripts involved in T-cell receptor, TFG-β, and inflammatory response signaling pathways (Klengel et al, 2013).”