Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring.
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.


METHODS
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.
Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Mental Health Care Center, PTSD Clinical Research Program and Laboratory of Clinical Neuroendocrinology/Neurochemistry, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA.|Fishberg Department of, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Rachel
R
Yehuda
Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Fishberg Department of, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nikolaos P
NP
Daskalakis
Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Fishberg Department of, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Amy
A
Lehrner
Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Fishberg Department of, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Frank
F
Desarnaud
Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Fishberg Department of, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Heather N
HN
Bader
Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Fishberg Department of, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Iouri
I
Makotkine
Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Fishberg Department of, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Janine D
JD
Flory
Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Fishberg Department of, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Linda M
LM
Bierer
Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.|Agency for Science, Technology and Research, Singapore Institute for Clinical Sciences, Singapore.
Michael J
MJ
Meaney
D032721:Adult Children / Q000523:psychology; D016022:Case-Control Studies; D016241:Child of Impaired Parents / Q000523:psychology; D019175:DNA Methylation; D003907:Dexamethasone; D044127:Epigenesis, Genetic / Q000235:genetics*; D005220:Fathers; D005260:Female; D040941:Heredity; D017767:Holocaust / Q000523:psychology*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009035:Mothers; D010912:Pituitary-Adrenal Function Tests; D011401:Promoter Regions, Genetic / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D013313:Stress Disorders, Post-Traumatic / Q000235:genetics*; D017741:Survivors / Q000523:psychology*
C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D006854:Hydrocortisone