title: 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.
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany. klengel@mpipsykl.mpg.de
authors.forename: Torsten
authors.initials: T
authors.lastname: Klengel
authors.forename: Divya
authors.initials: D
authors.lastname: Mehta
authors.forename: Christoph
authors.initials: C
authors.lastname: Anacker
authors.forename: Monika
authors.initials: M
authors.lastname: Rex-Haffner
authors.forename: Jens C
authors.initials: JC
authors.lastname: Pruessner
authors.forename: Carmine M
authors.initials: CM
authors.lastname: Pariante
authors.forename: Thaddeus W W
authors.initials: TW
authors.lastname: Pace
authors.forename: Kristina B
authors.initials: KB
authors.lastname: Mercer
authors.forename: Helen S
authors.initials: HS
authors.lastname: Mayberg
authors.forename: Bekh
authors.initials: B
authors.lastname: Bradley
authors.forename: Charles B
authors.initials: CB
authors.lastname: Nemeroff
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Christine M
authors.initials: CM
authors.lastname: Heim
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Ressler
authors.forename: Theo
authors.initials: T
authors.lastname: Rein
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
mesh_terms: D000328:Adult; D002460:Cell Line; D002648:Child; D002649:Child Abuse / Q000523:psychology; D015331:Cohort Studies; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics*; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005938:Glucocorticoids / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007438:Introns / Q000235:genetics; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D059906:Neuroimaging; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010755:Organophosphates / Q000378:metabolism; D020648:Peptide Elongation Factor 1 / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013313:Stress Disorders, Post-Traumatic / Q000097:blood / Q000209:etiology / Q000235:genetics*; D022021:Tacrolimus Binding Proteins / Q000235:genetics*; D014162:Transfection; D055815:Young Adult; D000099159:Tacrolimus Binding Protein 5
chemical_list: D003907:Dexamethasone; D005938:Glucocorticoids; D006854:Hydrocortisone; D010755:Organophosphates; D020648:Peptide Elongation Factor 1; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C009524:tributyl phosphate