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Articles   |    
Influences of Maternal and Paternal PTSD on Epigenetic Regulation of the Glucocorticoid Receptor Gene in Holocaust Survivor Offspring
Rachel Yehuda, Ph.D.; Nikolaos P. Daskalakis, M.D., Ph.D.; Amy Lehrner, Ph.D.; Frank Desarnaud, Ph.D.; Heather N. Bader, B.S.; Iouri Makotkine, M.D.; Janine D. Flory, Ph.D.; Linda M. Bierer, M.D.; Michael J. Meaney, Ph.D.
Am J Psychiatry 2014;171:872-880. doi:10.1176/appi.ajp.2014.13121571
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The authors report no financial relationships with commercial interests.

Drs. Yehuda, Daskalakis, and Lehrner contributed equally to this article.

Supported by a grant from NIMH (1RC1MH088101-01) and by grant UL1TR000067 from the National Center for Advancing Translational Sciences (NCATS), a component of NIH. NIMH, NIH, and NCATS had no role in the study design, in the collection, analysis, and interpretation of the data, in writing the study, or in the decision to submit the study for publication.

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.

Presented in part at the 29th Annual Meeting of the International Society for Traumatic Studies, Philadelphia, Nov. 7–9, 2013, and the 52nd Annual Meeting of the American College of Neuropsychopharmacology, Hollywood, Fla., Dec. 8–12, 2013.

Address correspondence to Dr. Yehuda (rachel.yehuda@va.gov).

Copyright © 2014 by the American Psychiatric Association

Received December 01, 2013; Revised February 07, 2014; Accepted February 27, 2014.

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.

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FIGURE 1. Percent Methylation in the Exon 1F Promoter of the Glucocorticoid Receptor Gene in Peripheral Blood Mononuclear Cells (PBMCs) in Offspringa

a Results are based on the presence or absence of maternal and paternal posttraumatic stress disorder, controlling for parental Holocaust exposure, age, smoking history, and PBMC type. The represented data (mean, standard deviation) are based on an analysis of covariance using raw data. The post hoc statistic (*) is from the analysis using transformed (natural logarithm) data.

FIGURE 2. Phenotypic Clustering Based on the Presence or Absence of Maternal and Paternal Posttraumatic Stress Disorder (PTSD)a

a Rows represent different phenotypes that are also presented in Table 2. Columns represent experimental groups (no parental PTSD, mother only PTSD, father only PTSD, both parents PTSD). The unsupervised hierarchical clustering is presented in dendrograms, with vertical dendrograms representing phenotypic clustering, horizontal dendrograms representing group clustering, and the dendrogram scales represent Euclidean distances. The heat map depicts phenotype-by-group clusters with the color scale based on a phenotype z-score, where blue represents a low score and red represents a high score. 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, which is presented only in panel B. BDI=Beck Depression Inventory; CTQ=Childhood Trauma Questionnaire; DES=Dissociative Experiences Scale; PPQ=Parental PTSD Questionnaire; RSQ=Relationship Scales Questionnaire; STAI=Spielberger State-Trait Anxiety Inventory.

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TABLE 1. Demographic and Clinical Characteristics of Offspring Based on the Presence or Absence of Maternal and Paternal Posttraumatic Stress Disorder (PTSD)
Table Footer Note

a Data indicate the current or lifetime Structured Clinical Interview for DSM-IV (SCID) diagnosis of major depressive disorder.

Table Footer Note

b Data indicate the current or lifetime SCID diagnosis of an axis I anxiety disorder.

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TABLE 2.Clinical Characteristics of Offspring Based on the Presence or Absence of Maternal and Paternal Posttraumatic Stress Disorder (PTSD)
Table Footer Note

a Analyses represent 2×2 analysis of variance of maternal and paternal PTSD on clinical outcomes, with statistics for main effects and the interaction term reported.

Table Footer Note

b The data represent the PPQ item, “I believe that I have psychological scars as a result of the fact that I was raised by parent(s) that survived the Holocaust.”

Table Footer Note

c The data represent the PPQ item, “I believe that I am more sensitive to violence and injustice because of my parents' experiences in the Holocaust.”

Table Footer Note

d The data represent the PPQ item, “I believe that I am more likely to be affected by stress than other individuals my age (who were not raised by Holocaust survivors).”

Table Footer Note

e The data represent the PPQ item: “Although I did not directly undergo the Holocaust, I have vicariously experienced and have been deeply troubled by the trauma of the Holocaust.”

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