title: Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation.
abstract: The involvement of epigenetic mechanisms in intergenerational transmission of stress effects has been demonstrated in animals but not in humans.
  
  
  
  Cytosine methylation within the gene encoding for FK506 binding protein 5 (FKBP5) was measured in Holocaust survivors (n = 32), their adult offspring (n = 22), and demographically comparable parent (n = 8) and offspring (n = 9) control subjects, respectively. Cytosine-phosphate-guanine sites for analysis were chosen based on their spatial proximity to the intron 7 glucocorticoid response elements.
  
  
  
  Holocaust exposure had an effect on FKBP5 methylation that was observed in exposed parents as well in their offspring. These effects were observed at bin 3/site 6. Interestingly, in Holocaust survivors, methylation at this site was higher in comparison with control subjects, whereas in Holocaust offspring, methylation was lower. Methylation levels for exposed parents and their offspring were significantly correlated. In contrast to the findings at bin 3/site 6, offspring methylation at bin 2/sites 3 to 5 was associated with childhood physical and sexual abuse in interaction with an FKBP5 risk allele previously associated with vulnerability to psychological consequences of childhood adversity. The findings suggest the possibility of site specificity to environmental influences, as sites in bins 3 and 2 were differentially associated with parental trauma and the offspring's own childhood trauma, respectively. FKBP5 methylation averaged across the three bins examined was associated with wake-up cortisol levels, indicating functional relevance of the methylation measures.
  
  
  
  This is the first demonstration of an association of preconception parental trauma with epigenetic alterations that is evident in both exposed parent and offspring, providing potential insight into how severe psychophysiological trauma can have intergenerational effects.
authors.affiliation: Traumatic Stress Studies Division, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York; Mental Health Care Center, PTSD Clinical Research Program & Laboratory of Clinical Neuroendocrinology and Neurochemistry, James J. Peters Veterans Affairs Medical Center, Bronx, New York. Electronic address: rachel.yehuda@va.gov.
authors.forename: Rachel
authors.initials: R
authors.lastname: Yehuda
authors.affiliation: Traumatic Stress Studies Division, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York; Mental Health Care Center, PTSD Clinical Research Program & Laboratory of Clinical Neuroendocrinology and Neurochemistry, James J. Peters Veterans Affairs Medical Center, Bronx, New York.
authors.forename: Nikolaos P
authors.initials: NP
authors.lastname: Daskalakis
authors.affiliation: Traumatic Stress Studies Division, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York; Mental Health Care Center, PTSD Clinical Research Program & Laboratory of Clinical Neuroendocrinology and Neurochemistry, James J. Peters Veterans Affairs Medical Center, Bronx, New York.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Bierer
authors.affiliation: Traumatic Stress Studies Division, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York; Mental Health Care Center, PTSD Clinical Research Program & Laboratory of Clinical Neuroendocrinology and Neurochemistry, James J. Peters Veterans Affairs Medical Center, Bronx, New York.
authors.forename: Heather N
authors.initials: HN
authors.lastname: Bader
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Torsten
authors.initials: T
authors.lastname: Klengel
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany; HMNC Holding GmbH, Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
mesh_terms: D032721:Adult Children / Q000523:psychology; D016241:Child of Impaired Parents; D015331:Cohort Studies; D003596:Cytosine; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D017767:Holocaust / Q000523:psychology; D006801:Humans; D008297:Male; D010290:Parents; D011569:Psychiatric Status Rating Scales; D013313:Stress Disorders, Post-Traumatic / Q000235:genetics*; D011795:Surveys and Questionnaires; D017741:Survivors / Q000523:psychology; D022021:Tacrolimus Binding Proteins / Q000235:genetics*; D000099159:Tacrolimus Binding Protein 5
chemical_list: D003596:Cytosine; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5
keywords: Cortisol; Epigenetics; FKBP5; Intergenerational; PTSD; Stress