Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring

Abstract

Objective: Differential effects of maternal and paternal posttraumatic stress disorder (PTSD) have been observed in adult offspring of Holocaust survivors in both glucocorticoid receptor sensitivity and vulnerability to psychiatric disorder. The authors examined the relative influences of maternal and paternal PTSD on DNA methylation of the exon 1F promoter of the glucocorticoid receptor (GR-1F) gene (NR3C1) in peripheral blood mononuclear cells and its relationship to glucocorticoid receptor sensitivity in Holocaust offspring.

Method: Adult offspring with at least one Holocaust survivor parent (N=80) and demographically similar participants without parental Holocaust exposure or parental PTSD (N=15) completed clinical interviews, self-report measures, and biological procedures. Blood samples were collected for analysis of GR-1F promoter methylation and of cortisol levels in response to low-dose dexamethasone, and two-way analysis of covariance was performed using maternal and paternal PTSD as main effects. Hierarchical clustering analysis was used to permit visualization of maternal compared with paternal PTSD effects on clinical variables and GR-1F promoter methylation.

Results: A significant interaction demonstrated that in the absence of maternal PTSD, offspring with paternal PTSD showed higher GR-1F promoter methylation, whereas offspring with both maternal and paternal PTSD showed lower methylation. Lower GR-1F promoter methylation was significantly associated with greater postdexamethasone cortisol suppression. The clustering analysis revealed that maternal and paternal PTSD effects were differentially associated with clinical indicators and GR-1F promoter methylation.

Conclusions: This is the first study to demonstrate alterations of GR-1F promoter methylation in relation to parental PTSD and neuroendocrine outcomes. The moderation of paternal PTSD effects by maternal PTSD suggests different mechanisms for the intergenerational transmission of trauma-related vulnerabilities.

Figure 1. Percent methylation in the exon 1_F promoter of the glucocorticoid receptor gene (GR-1_F promoter) in Peripheral Blood Mononuclear Cells (PBMCs)

based on the presence or absence of maternal and paternal PTSD, controlling for parental Holocaust exposure, age, smoking history and PBMC-type. The represented data (mean ± SD) are based on an analysis of co-variance using raw data. The post-hoc statistic was from the analysis using transformed (natural logarithm) data.

Figure 2. Phenotypic clustering based on the presence or absence of maternal and paternal PTSD

The unsupervised hierarchical clustering is presented in dendrograms with vertical dendrograms representing phenotypic clustering, horizontal dendrograms representing group clustering and the scales reprsent Euclidean distance. A heatmap depicts phenotype-by-group-clusters with the color scale based on a z-score, where blue represents low score and red represents high. Rows represent different phenotypes that are also presented in Table 2. Columns represent experimental groups. Panel A and panel B contain the same phenotypic variables with the exception of percent methylation in the exon 1F promoter of the glucocorticoid receptor gene (GR-1_F promoter), which is presented only in panel B.