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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Cell Line
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Child
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Child Abuse / psychology
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Cohort Studies
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DNA Methylation / drug effects
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DNA Methylation / genetics*
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Dexamethasone / pharmacology
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Female
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Gene Expression Regulation
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Gene Frequency
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Gene-Environment Interaction*
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Genetic Predisposition to Disease*
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Genotype
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Glucocorticoids / chemistry
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Glucocorticoids / pharmacology
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HEK293 Cells
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Hippocampus / cytology
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Humans
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Hydrocortisone / blood
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Introns / genetics
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Logistic Models
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Male
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Middle Aged
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Models, Molecular
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Neuroimaging
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Neurons / drug effects
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Neurons / metabolism
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Organophosphates / metabolism
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Peptide Elongation Factor 1 / genetics
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Peptide Elongation Factor 1 / metabolism
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Polymorphism, Single Nucleotide / genetics*
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Stress Disorders, Post-Traumatic / blood
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Stress Disorders, Post-Traumatic / etiology
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Stress Disorders, Post-Traumatic / genetics*
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Tacrolimus Binding Proteins / genetics*
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Transfection
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Young Adult
Substances
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Glucocorticoids
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Organophosphates
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Peptide Elongation Factor 1
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Dexamethasone
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tributyl phosphate
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Tacrolimus Binding Proteins
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tacrolimus binding protein 5
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Hydrocortisone