These epigenetic studies in targeted genes suggest that genes might be altered downstream, and it is appropriate to follow-up with genome-wide investigations of gene expression to determine pathways involved. Differences in DNA methylation (DNAm) in an intronic region of the FK506 binding protein 51 gene ( FKBP5) have been associated with parental Holocaust exposure and maternal age at Holocaust exposure, while DNAm changes in a promoter of the GC receptor (GR) gene were in opposite directions for offspring with maternal vs.

Studies examining the putative molecular basis of the strong GC-related signals observed in association with parental trauma exposure, have focused on epigenetic alterations of stress related genes in blood.

These studies have underscored the importance of parental symptoms, sex, and age at exposure, as well as offspring sex, experiences and symptoms as potential contributors to the presence and direction of dysregulated biological findings observed in offspring. Studies on candidate biological systems have revealed alterations in basal cortisol excretion, pituitary and leukocyte glucocorticoid (GC) sensitivity, and GC metabolism of offspring, many of which are similar to those associated with trauma survivors with PTSD, mood and anxiety disorders. Similar associations were described in studies of Cambodian and Rwandan genocides. Adult offspring of Holocaust survivors were shown to have more symptoms of anxiety, depression and PTSD than demographically-similar offspring of Jewish parents who were not exposed to the Holocaust. Parental traumatic exposures can affect physical and mental health of offspring. To conclude, this study identified a set of glucocorticoid and immune-related genes in association with parental Holocaust exposure with differential effects based on parental exposure-related factors. The top gene across all analyses was MMP8, encoding the matrix metalloproteinase 8, which is a regulator of innate immunity. Moreover, the DEGs associated with parental Holocaust exposure were enriched for glucocorticoid-regulated genes and immune pathways with some of these genes mediating the effects of parental Holocaust exposure on C-reactive protein. Similarly, fold changes of shared DEGs associated with maternal PTSD and paternal PTSD were in opposite directions, while fold changes of shared DEGs associated with both maternal and paternal Holocaust exposure or associated with both maternal and paternal age at Holocaust exposure were in the same direction. When both parental Holocaust exposure and maternal age at Holocaust exposure shared DEGs, fold changes were in the opposite direction.

Forty-two differentially expressed genes (DEGs) were identified in association with parental Holocaust exposure (FDR-adjusted p < 0.05) most of these genes were downregulated and co-expressed in a gene network related to immune cell functions. This study reports the association between parental Holocaust exposure and genome-wide gene expression in peripheral blood mononuclear cells (PBMC) from 77 Holocaust survivor offspring and 15 comparison subjects. Offspring of trauma survivors are more likely to develop PTSD, mood, and anxiety disorders and demonstrate endocrine and molecular alterations compared to controls.

Intergenerational trauma cambodia