Holocaust Exposure and Intergenerational Impact via FKBP5 Methylation

Scientists know that, in animal models, stress can produce epigenetic alterations that are inheritable by offspring. This could be key to understanding why the children of trauma survivors are more vulnerable to symptoms of post-traumatic stress disorder (PTSD) and other mood and/or anxiety disorders. One protein, FK506 binding protein 5 (FKBP5), regulates glucocorticoid receptor sensitivity and has been linked to PTSD and major depression. Indeed, researchers have previously used single nucleotide polymorphisms of this protein to predict both PTSD and major depression in the presence of early trauma, possibly as a result of methylation.^1-3

Recently, Yehuda et al. (2015) investigated differential methylation of FKBP5 (intron 7) in Holocaust survivors and their children, as well as in demographically matched, non-exposed parent/offspring pairs (control subjects).⁴ The team also considered the offspring’s own experience of trauma (childhood adversity).

When compared with parent control subjects, the Holocaust survivors demonstrated 10% upregulation of methylation at bin 3/site 6. Adding FKBP5 risk allele presence/absence as a covariate did not change the results, indicating that this methylation resulted from exposure. The team observed no differences between survivors and controls for bins 1 and 2.

The same analysis applied to survivor offspring, and control offspring revealed 7.7% downregulation of methylation at bin 3/site 6 for survivor offspring. This result did not change with the additions of covariates “presence of lifetime PTSD in offspring” or “childhood trauma,” but it did reduce when they controlled for parental PTSD, indicating the downregulation resulted from parental influence.

The team confirmed via linear regression that parental Holocaust exposure could predict offspring bin 3/site 6 methylation. The following were not predictors and did not impact the significance of Holocaust exposure at this localization: parental PTSD, FKBP5 risk allele or childhood adversity (neither the Childhood Trauma Questionnaire total score nor emotional abuse specifically). The team also measured awakening and bedtime salivary cortisol levels and observed a significant negative correlation between wake-up cortisol and FKBP5 Intron 7 methylation for offspring.

Overall, the team reports that Holocaust survivors and their offspring experience differential methylation on the same site but in opposite directions. They indicate that this is the first evidence of epigenetic changes occurring as a result of preconception stress. They were able to attribute bin 3/site 6 methylation to Holocaust exposure in the parent generation while dissociating it from independent genetic impacts in the offspring generation, including FKBP5 risk allele presence/absence, offspring trauma exposure and offspring psychopathology. The team contrasted these findings with a previous study³ (and their replication of it) to demonstrate that direct trauma exposure by offspring impacted a different location (bin 2/sites 3–5).

Yehuda et al. indicate that further studies involving other high-risk trauma survivors and several generations of offspring could help disentangle exposure effects and specific modes of epigenetic inheritance, including gamete transmission and in utero effects. They further suggest that early detection of epigenetic marks could offer a means to identify high-risk individuals in order to apply strategies to prevent the intergenerational effects of trauma exposure.

 

References

1. Binder, E.B., et al. (2008) “Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults,” JAMA, 299 (pp. 1291–1305).

2. Koenen, K. C. and Uddin, M. (2010) “FKBP5 polymorphisms modify the effects of childhood trauma,” Neuropsychopharmacology, 35 (pp. 1623–1624).

3. Klengel, T. et al. (2013) “Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions,” Nature Neuroscience, 16 (pp. 33–41).

4. Yehuda, R. (2015) “Holocaust exposure induced intergenerational effects on FKBP5 methylation,” Biological Psychiatry. doi: 10.1016/j.biopsych.2015.08.005.