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Data from all 187 participants were used to test associations of parental and offspring characteristics with FKBP5 methylation. Thus, 156 participants (125 offspring and 31 control subjects) made up an independent replication sample to test methylation differences between Holocaust offspring and control subjects. Study 2 contributed 77 offspring and 14 control subjects. The remaining 48 offspring and 17 control subjects constitute sample 1b. Data for 22 Holocaust offspring and nine control subjects from study 1 were previously published ( 5) and are designated as sample 1a. Participants were recruited for two studies (study 1, 2001–2006 study 2, 2009–2011) designed to examine endocrine and molecular correlates of parental PTSD in five groups (Holocaust offspring with and without maternal and/or paternal PTSD, and comparison subjects). The present study was conducted to replicate and extend the previous findings in a larger sample and to determine salient correlates of the effect. Increased methylation at FKBP5 intron 7, specifically at CpG site 6, was observed in Holocaust survivors, but lower methylation at this site was seen in their offspring compared with respective control subjects ( 5).īecause the sample size in our original pilot study ( 5) was small (constrained by availability of DNA from both parents and their offspring), potential contributors to FKBP5 methylation, such as parental sex, age at exposure, and PTSD status or offspring trauma history or psychopathology, could not be examined. Functional epigenetic alterations to FKBP5 have been observed in association with psychiatric vulnerability, resilience, and symptom improvement in PTSD ( 7, 9, 11). FKBP5 was identified in the first genome-wide transcriptomics study of PTSD as one of several mRNAs that distinguished trauma-exposed persons with and without PTSD, independent of FKBP5 genotype ( 10). The FKBP5 protein moderates translocation of the bound glucocorticoid receptor and is a regulator of glucocorticoid receptor responsivity ( 7, 9).
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Changes in DNA methylation of the NR3C1 promoter, glucocorticoid receptor responsiveness, and ambient cortisol levels have been demonstrated in offspring of Holocaust survivors in relation to parental sex and PTSD ( 8), prompting a preliminary study examining DNA methylation on a region of the FKBP5 gene containing functional glucocorticoid response elements ( 5).
![intergenerational trauma holocaust intergenerational trauma holocaust](https://image1.slideserve.com/2774211/holocaust-studies-l.jpg)
The HPA axis is subject to early developmental programming, including via epigenetic alterations to FKBP5 and NR3C1 ( 6, 7). Initial examination of the biological correlates of parental Holocaust trauma focused on the hypothalamic-pituitary-adrenal (HPA) axis and on two genes related to glucocorticoid signaling: NR3C1, encoding the glucocorticoid receptor, and FK506 binding protein 5 ( FKBP5), encoding a glucocorticoid receptor co-chaperone that has been shown to be altered in PTSD ( 4, 5).
![intergenerational trauma holocaust intergenerational trauma holocaust](https://holocaustcenter.jfcs.org/app/uploads/2019/03/Intergenerational-Trauma-1.jpg)
Many putative mechanisms have been proposed to explain the effects of parental trauma, including impaired attachment and parenting, in utero perturbations, and alterations to the germline of exposed parents ( 3). Similar consequences of parental exposure to combat, displacement, and genocides have also been reported ( 2, 3). That offspring may be affected by parental trauma exposures occurring prior to conception was initially supported by an increased prevalence of posttraumatic stress disorder (PTSD) and of mood and anxiety disorders in offspring of Holocaust survivors ( 1).