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Influences of Maternal and Paternal PTSD on Epigenetic Regulation of the Glucocorticoid Receptor Gene in Holocaust Survivor Offspring
Open accessAbstract
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.
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“Of the studies investigating specifically NR3C1, four out of six reported higher DNA methylation in offspring after trauma exposure [86,91,95,98]”
From Biological Embedding of Early-Life Adversity and a Scoping Review of the Evidence for Intergenerational Epigenetic Transmission of Stress and Trauma in Humans (2023) · cites this paper as [95]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Studies of Holocaust survivors and their offspring demonstrate differential DNA methylation of key HPA-axis genes, including NR3C1 and FKBP5, corresponding with variation in glucocorticoid receptor sensitivity and cortisol feedback regulation (82, 83).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [82]
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“Functional alterations in cortisol metabolism, including reduced cortisol excretion in survivors and increased activity of cortisol-inactivating enzymes in offspring, have also been described (82, 85).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [82]
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“Across multiple trauma contexts, altered methylation of NR3C1 has been reported, including genocide exposure, childhood maltreatment, and natural disasters (10, 82, 88, 89).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [82]
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“The majority of the studies looked at only maternal transmission, but four considered both maternal and paternal [83,94,95,102], and two focused only on fathers [97,104].”
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“There were six studies of trauma or PTSD following war, including two studies of Holocaust survivors [83,94,95], two studies on the Rwandan genocide [90,91], and one each from the Kosovo War [96] and Vietnam veterans [97].”
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“Across survivor populations and their descendants, research suggests coordinated involvement of stress-response regulation, neurodevelopmental signaling, and behavioral adaptation (7, 82–100).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [82]
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“Divergent patterns have been observed depending on parental PTSD status, with paternal PTSD in the absence of maternal PTSD associated with increased methylation of NR3C1 in offspring, whereas combined maternal and paternal PTSD has been associated with decreased methylation (82).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [82]
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“Many investigations focus on historically defined trauma-exposed populations, including Holocaust survivors, Rwandan genocide survivors, and Alaska Native communities (8, 82, 98).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [82]
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“Differential methylation of the glucocorticoid receptor (GR) gene associated with maternal behavior has been observed in F1 in rodents at Nr3c1 exon 1 7 promoter (16) and in human offspring with parental PTSD at the ortholog NR3C1 exon 1 F promoter (24).”
From Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation (2016) · cites this paper as [24]
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“Lower GR 1F promoter methylation was significantly associated with greater GR sensitivity, as indicated by greater post-dexamethasone cortisol suppression.”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [126]
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“In parallel with the neuroendocrine observations, the results of these analyses indicated a significant interaction of maternal and paternal PTSD on GR gene methylation 126 .”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [126]
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“This possibility is consistent with clinical, neuroendocrine and epigenetic findings, in which maternal and paternal PTSD predicted different psychiatric and biological outcomes in offspring 28,126 .”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [126]
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“The interaction demonstrated that, in the absence of maternal PTSD, offspring with paternal PTSD showed higher GR promoter methylation, whereas offspring with both maternal and paternal PTSD showed lower methylation of this promoter region.”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [126]
In the citing paper
“We recently addressed this issue in PTSD patients and provide evidence suggesting that variation in the methylation of the exon 1F GR promoter associated with PTSD symptoms and predicted treatment outcome.135-137”
From Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function (2014) · cites this paper as [136]
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Metadata
- Authors
- Yehuda, R., Daskalakis, N. P., Lehrner, A., Desarnaud, F., Bader, H. N., Makotkine, I., Flory, J. D., Bierer, L. M., & Meaney, M. J.
- Affiliations
- Agency for Science, Technology and Research (SG)
- From the James J. Peters Veterans Affairs Medical Center, Bronx, N.Y.; Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York; the Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal; and the Agency for Science, Technology, and Research, Singapore Institute for Clinical Sciences, Singapore.
- Corresponding author
- Yehuda, Rachel
- ORCID
- Venue
- American Journal of Psychiatry
- Published
- 2014-08
- Volume
- 171
- Issue
- 8
- Pages
- 872-880
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC4127390
- OpenAlex
- W2137209519
- Cited by
- 514
- References
- 37
- Citations by year
- 2026: 16 · 2025: 46 · 2024: 37 · 2023: 38 · 2022: 36 · 2021: 42 · 2020: 75 · 2019: 34 · 2018: 45 · 2017: 46 · 2016: 38 · 2015: 44 · 2014: 14
- FWCI
- 55.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000067)
- National Institute of Mental Health (RC1MH088101)
- National Center for Research Resources (M01RR000071)
- National Center for Advancing Translational Sciences
- Topics
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- post-traumatic stress disorder, Holocaust survivors, glucocorticoid receptor, NR3C1, DNA methylation, intergenerational trauma, maternal PTSD, cortisol suppression, dexamethasone, glucocorticoid receptor sensitivity, neuroendocrine function
- MeSH terms
- Dexamethasone, Fathers, Female, Humans, Hydrocortisone, Leukocytes, Mononuclear, Male, Middle Aged, Mothers, Pituitary-Adrenal Function Tests, Promoter Regions, Genetic, Receptors, Glucocorticoid, Stress Disorders, Post-Traumatic, Case-Control Studies, Child of Impaired Parents, Survivors, Holocaust, DNA Methylation, Adult Children, Heredity, Epigenesis, Genetic
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