Intergenerational Transmission of Stress Vulnerability and Resilience Following Trauma

Novel insights into the genetics of autism
Novel insights into the genetics of autism
Extreme trauma affects FKBP5 methylation in survivors of the Holocaust as well as in their offspring.

Environmental conditions modify the expression of genes without changing the DNA sequence. These so-called epigenetic modifications, just like a discrete sequence of DNA nucleotides, can be transmitted from generation to generation. In other words, the environment has an influence over heritable changes in phenotype.1 Epigenetic inheritance is known to play a role in the effects of nutrition and undernutrition on increased risk of cardiovascular disease, diabetes, and neonatal adiposity across generations.2,3 A similar concept may also explain the higher prevalence of lifetime neuropsychiatric illness—including posttraumatic stress disorder (PTSD), and mood and anxiety disorders—in offspring of Holocaust survivors, as well as in offspring of parents and grandparents who were diagnosed with major depressive disorder (MDD) compared to that in a control population.4,5

Epigenetic alterations that occur as a consequence of exposure to traumatic stress and that are then transmitted across generations to influence the development of neuropsychiatric symptoms in offspring have been documented in rodents but not in humans. In 2015, a team of investigators led by Rachel Yehuda, PhD, a professor of psychiatry and neuroscience, and director of the Traumatic Stress Studies Division at the Mount Sinai School of Medicine in New York, provided direct evidence that parental trauma in humans is associated with epigenetic modifications, such as DNA methylation, which are seen in both Holocaust survivors and their adult offspring.6 (DNA methylation refers to the addition of a methyl group to DNA and is mainly associated with repression of gene expression.)

The neuroendocrine system, via activation of the hypothalamic-pituitary-adrenal (HPA) axis and subsequent release of glucocorticoids from the adrenal cortex, is crucial in regulating the physiologic stress response in mammals. Dysregulation of the HPA axis, which can be associated with abnormal cortisol production or altered glucocorticoid receptor (GR) sensitivity, contributes to enhanced stress vulnerability and susceptibility to developing PTSD. In addition, a number of different genes can modify HPA axis reactivity, and polymorphisms in HPA-axis-related genes can regulate both GR sensitivity and cortisol levels.7

Video news update: Dr. Rachel Yehuda speaks about trauma and memories. Watch now.

Clinical studies have implicated FK506 binding protein 51 (FKBP5), a co-chaperone of the GR, in stress-related disorders. Also, FKBP5 alters GR complex affinity for cortisol and decreases overall GR signaling. It is worth noting that human genetic studies have revealed interactions between FKBP5 single-nucleotide polymorphisms and early childhood adversity that significantly predict the onset of PTSD. Taken together, these biological pathways may contribute to the heightened risk of developing stress-related psychiatric disorders.7

In their 2015 study, Dr Yehuda and colleagues showed that extreme trauma affects FKBP5 methylation in surviving parents as well as in their offspring. Severe parental trauma-induced methylation changes, however, were in opposite directions. When compared to control participants, methylation was higher in survivors of the Holocaust but was lower in their adult offspring. “The directional difference in methylation between Holocaust survivors and their offspring was unexpected but may reflect an intergeneration biological accommodation,” the authors concluded.6

In a conversation with Psychiatry Advisor, Dr Yehuda added, “It’s really important to understand that epigenetic effects are a combination of negative effects and positive effects, such as accommodations and adaptations, which might be transmitted from parents to their offspring. If a parent is able to transmit an effect to offspring, the reason may not be to perpetuate a negative effect of trauma but to prepare the offspring and give them tools to better cope with the environment. This is a very empowering concept that makes psychotherapy extremely valuable.”

The authors also noted that “it is not possible to infer mechanisms of transmission from these data.” However, “FKBP5 methylation was associated with wake-up cortisol levels, indicating functional relevance of the methylation measures.”6

Although it is evident that PTSD is caused by a complex interplay between genetic and environmental components, association studies and epidemiologic analyses are unable to detect causative biological mechanisms that underlie its development. Thus, nonhuman animal models are essential to address the biological basis of psychiatric illness because they allow rigorous control of both genetic and environmental variables. Although the FKBP5 methylation findings were recently replicated in a monkey model, Dr Yehuda mentioned that these results are yet to be published.

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1. van Otterdijk SD, Michels KB. Transgenerational epigenetic inheritance in mammals: how good is the evidence? FASEB J. 2016: fj.201500083. [Epub ahead of print]

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3. Painter RC, Osmond C, Gluckman P, et al. Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life. BJOG. 2008;115:1243-1249.

4. Yehuda R, Schmeidler J, Wainberg M, et al. Vulnerability to posttraumatic stress disorder in adult offspring of Holocaust survivors. Am J Psychiatry. 1998;155:1163-1171.

5. Weissman MM, Wickramaratne P, Nomura Y, et al. Families at high and low risk for depression: a 3-generation study. Arch Gen Psychiatry. 2005;62:29-36.

6. Yehuda R, Daskalakis NP, Bierer LM, et al. Holocaust exposure induced intergenerational effects on FKBP5 methylation. Biol Psychiatry. 2015: 10.1016/j.biopsych.2015.08.005. [Epub ahead of print]

7. Mehta D, Binder EB. Gene x environment vulnerability factors for PTSD: the HPA-axis. Neuropharmacology. 2012;62:654-62.