Skip to main content Accessibility help

Dynamic stress-related epigenetic regulation of the glucocorticoid receptor gene promoter during early development: The role of child maltreatment

  • Justin Parent (a1) (a2) (a3), Stephanie H. Parade (a1) (a2), Laura E. Laumann (a4), Kathryn K. Ridout (a1) (a4), Bao-Zhu Yang (a5), Carmen J. Marsit (a6), Ronald Seifer (a1) (a2) and Audrey R. Tyrka (a1) (a4)...


Epigenetics processes may play a vital role in the biological embedding of early environmental adversity and the development of psychopathology. Accumulating evidence suggests that maltreatment is linked to methylation of the glucocorticoid receptor gene, nuclear receptor subfamily 3, group C, member 1 (NR3C1), which is a key regulator of the hypothalamus–pituitary–adrenal axis. However, prior work has been exclusively cross-sectional, greatly constraining our understanding of stress-related epigenetic processes over time. In the current study, we examined the effect of maltreatment and other adversity on change in NR3C1 methylation among at-risk preschoolers to begin to characterize within-child epigenetic changes during this sensitive developmental period. Participants were 260 preschoolers (3–5 years old, 53.8% female), including 51.5% with moderate to severe maltreatment in the past 6 months. Child protection records, semistructured interviews, and parent reports were used to assess child stress exposure. Methylation of exons 1D and 1F of NR3C1 via saliva DNA were measured at two time points approximately 6 months apart. Results indicate that maltreated children evidence higher baseline levels of NR3C1 methylation, significant decreases in methylation over time, and then at follow-up, lower levels of methylation, relative to nonmaltreated preschoolers. Findings from the current study highlight the complex nature of stress-related epigenetic processes during early development.


Corresponding author

Address correspondence and reprint requests to: Audrey R. Tyrka, Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Department of Psychiatry and Human Behavior, Alpert Medical School, Brown University, Providence, RI 02903; E-mail:


Hide All

This research was supported by Grant R01 MH083704 (to A.R.T.) and R25 MH101076 (K.K.R.) from the National Institute of Mental Health. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the NIMH. We are grateful to the children and families who participated in this study, and we thank Hasbro Children's Hospital, Rhode Island Head Start, and the Rhode Island Department of Children, Youth, and Families for assisting in recruitment of study participants. We also thank Brittney Josefson and the numerous other research assistants who contributed to this project, and Asi Polly Gobin for data management. Isolation of DNA and genotyping were done in the laboratory of Joel Gelernter, MD, and we are grateful to Dr. Gelernter and his staff for their contribution.



Hide All
Barden, N. (2004). Implication of the hypothalamic-pituitary-adrenal axis in the physiopathology of depression. Journal of Psychiatry and Neuroscience, 29, 185193.
Barnett, D., Manly, J. T., & Cicchetti, D. (1993). Defining child maltreatment: The interface between policy and research. In Cicchetti, D. & Toth, S. L. (Eds.), Child abuse, child development, and social policy (pp. 773). Norwood, NJ: Ablex.
Bird, A. (2002). DNA methylation patterns and epigenetic memory. Genes & Development, 16, 621. doi:10.1101/gad.947102
Boyce, W. T., & Kobor, M. S. (2015). Development and the epigenome: The “synapse” of gene environment interplay. Developmental Science, 18, 123. doi:10.1111/desc.12282
Braquehais, M. D., Picouto, M. D., Casas, M., & Sher, L. (2012). Hypothalamic–pituitary–adrenal axis dysfunction as a neurobiological correlate of emotion dysregulation in adolescent suicide. World Journal of Pediatrics, 8, 197206. doi:10.1007/s12519-012-0358-0
Breton, C. V., Marsit, C. J., Faustman, E., Nadeau, K., Goodrich, J. M., Dolinoy, D. C., … Yousefi, P. (2017). Small-magnitude effect sizes in epigenetic end points are important in children's environmental health studies: The Children's Environmental Health and Disease Prevention Research Center's Epigenetics Working Group. Environmental Health Perspectives, 125, 511526. doi:10.1289/EHP595
Cicchetti, D., & Toth, S. L. (2016). Child maltreatment and developmental psychopathology: A multilevel perspective. In Cicchetti, D. (Ed.), Developmental psychopathology (Vol. 3, 3rd ed., pp. 457512). Hoboken, NJ: Wiley.
Cohen, S., Janicki-Deverts, D., & Miller, G. E. (2007). Psychological stress and disease. Journal of the American Medical Association, 298, 16851687. doi:10.1001/jama.298.14.1685
Conradt, E., Hawes, K., Guerin, D., Armstrong, D. A., Marsit, C. J., Tronick, E., & Lester, B. M. (2016). The contributions of maternal sensitivity and maternal depressive symptoms to epigenetic processes and neuroendocrine functioning. Child Development, 87, 7385. doi:10.1111/cdev.12483
Conradt, E., Lester, B. M., Appleton, A. A., Armstrong, D. A., & Marsit, C. J. (2013). The roles of DNA methylation of NR3C1 and 11beta-HSD2 and exposure to maternal mood disorder in utero on newborn neurobehavior. Epigenetics, 8, 13211329. doi:10.4161/epi.26634
Dadds, M. R., Moul, C., Hawes, D. J., Mendoza Diaz, A., & Brennan, J. (2015). Individual differences in childhood behavior disorders associated with epigenetic modulation of the cortisol receptor gene. Child Development, 86, 13111320. doi:10.1111/cdev.12391
Daskalakis, N. P., & Yehuda, R. (2014). Site-specific methylation changes in the glucocorticoid receptor exon 1F promoter in relation to life adversity: Systematic of contributing factors. Frontiers in Neuroscience, 8, 369. doi:10.3389/fnins.2014.00369
de Kloet, E. R., Joëls, M., & Holsboer, F. (2005). Stress and the brain: From adaptation to disease. Nature Reviews Neuroscience, 6, 463475. doi:10.1038/nrn1683
Doom, J. R., & Gunnar, M. R. (2013). Stress physiology and developmental psychopathology: Past, present, and future. Development and Psychopathology, 25, 13591373. doi:10.1017/S0954579413000667
Farré, P., Jones, M. J., Meaney, M. J., Emberly, E., Turecki, G., & Kobor, M. S. (2015). Concordant and discordant DNA methylation signatures of aging in human blood and brain. Epigenetics & Chromatin, 8, 19. doi:10.1186/s13072-015-0011-y
Heim, C., & Binder, E. B. (2012). Current research trends in early life stress and depression: Review of human studies on sensitive periods, gene-environment interactions, and epigenetics. Experimental Neurology, 233, 102111. doi:10.1016/j.expneurol.2011.10.032
Herman, J. P., McKlveen, J. M., Solomon, M. B., Carvalho-Netto, E., & Myers, B. (2012). Neural regulation of the stress response: Glucocorticoid feedback mechanisms. Brazilian Journal of Medical and Biological Research, 45, 292298. doi:10.1590/S0100-879X2012007500041
Hompes, T., Izzi, B., Gellens, E., Morreels, M., Fieuws, S., Pexsters, A., … Claes, S. (2013). Investigating the influence of maternal cortisol and emotional state during pregnancy on the DNA methylation status of the glucocorticoid receptor gene (NR3C1) promoter region in cord blood. Journal of Psychiatric Research, 47, 880891. doi:10.1016/j.jpsychires.2013.03.009
Hu, L., & Bentler, P. (1999). Cutoff criteria for fit indices in covariance structure analysis: Conventional criteria versus new alternatives. Structural Equation Modeling, 6, 155. doi:10.1080/10705519909540118
Jones, M. J., Moore, S. R., & Kobor, M. S. (in press). Principles and challenges of applying epigenetic epidemiology to psychology. Annual Review of Psychology.
Kadmiel, M., & Cidlowski, J. A. (2013). Glucocorticoid receptor signaling in health and disease. Trends in Pharmacological Sciences, 34, 518530. doi:10.1016/
Kertes, D. A., Kamin, H. S., Hughes, D. A., Rodney, N. C., Bhatt, S., & Mulligan, C. J. (2016). Prenatal maternal stress predicts methylation of genes regulating the hypothalamic-pituitary-adrenocortical system in mothers and newborns in the Democratic Republic of Congo. Child Development, 87, 6172. doi:10.1111/cdev.12487
Kosten, T. A., Huang, W., & Nielsen, D. A. (2014). Sex and litter effects on anxiety and DNA methylation levels of stress and neurotrophin genes in adolescent rats. Developmental Psychobiology, 56, 392406. doi:10.1002/dev.21106
Kosten, T. A., & Nielsen, D. A. (2014). Litter and sex effects on maternal behavior and DNA methylation of the Nr3c1 exon 17 promoter gene in hippocampus and cerebellum. International Journal of Developmental Neuroscience, 36, 512. doi:10.1016/j.ijdevneu.2014.03.010
Kundakovic, M., Lim, S., Gudsnuk, K., & Champagne, F. A. (2013). Sex-specific and strain dependent effects of early life adversity on behavioral and epigenetic outcomes. Frontiers in Psychiatry, 4, 78.
Labonte, B., Azoulay, N., Yerko, V., Turecki, G., & Brunet, A. (2014). Epigenetic modulation of glucocorticoid receptors in posttraumatic stress disorder. Translational Psychiatry, 4, e368. doi:10.3389/fpsyt.2013.00078
Labonte, B., Yerko, V., Gross, J., Mechawar, N., Meaney, M. J., Szyf, M., Turecki, G. (2012). Differential glucocorticoid receptor exon 1(B), 1(C), and 1(H) expression and methylation in suicide completers with a history of childhood abuse. Biological Psychiatry, 72, 4148. doi:10.1016/j.biopsych.2012.01.034
Laryea, G., Muglia, L., Arnett, M., & Muglia, L. J. (2015). Dissection of glucocorticoid receptor mediated inhibition of the hypothalamic-pituitary-adrenal axis by gene targeting in mice. Frontiers in Neuroendocrinology, 36, 150164. doi:10.1016/j.yfrne.2014.09.002
Leenen, F. A., Muller, C. P., & Turner, J. D. (2016). DNA methylation: Conducting the orchestra from exposure to phenotype? Clinical Epigenetics, 8, 92. doi:10.1186/s13148-016-0256-8
Lester, B. M., Conradt, E., & Marsit, C. (2016). Introduction to the special section on epigenetics. Child Development, 87, 2937. doi:10.1111/cdev.12489
Lévesque, M. L., Casey, K. F., Szyf, M., Ismaylova, E., Ly, V., Verner, M., … Booij, L. (2014). Genomewide DNA methylation variability in adolescent monozygotic twins followed since birth. Epigenetics, 9, 14101421. doi:10.4161/15592294.2014.970060
Lillycrop, K. A., Slater-Jefferies, J. L., Hanson, M. A., Godfrey, K. M., Jackson, A. A., & Burdge, G. C. (2007). Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications. British Journal of Nutrition, 97, 10641073. doi:10.1017/S000711450769196X
McArdle, J. J. (2009). Latent variable modeling of differences and changes with longitudinal data. Annual Review of Psychology, 60, 577605. doi:10.1146/annurev.psych.60.110707.163612
McCrory, E. J., & Viding, E. (2015). The theory of latent vulnerability: Reconceptualizing the link between childhood maltreatment and psychiatric disorder. Development and Psychopathology, 27, 493505. doi:10.1017/S0954579415000115
McEwen, B. S., Bowles, N. P., Gray, J. D., Hill, M. N., Hunter, R. G., Karatsoreos, I. N., & Nasca, C. (2015). Mechanisms of stress in the brain. Nature Neuroscience, 18, 13531363. doi:10.1038/nn.4086
McGowan, P. O., Sasaki, A., D'Alessio, A. C., Dymov, S., Labonte, B., Szyf, M., … Menaey, M. J. (2009). Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nature Neuroscience, 12, 342348. doi:10.1038/nn.2270
McGregor, K., Labbe, A., & Greenwood, C. M. (2017). Response to: Correcting for cell-type effects in DNA methylation studies: Reference-based method outperforms latent variable approaches in empirical studies. Genome Biology, 18, 25. doi:10.1186/s13059-017-1149-7
Meaney, M. J. (2010). Epigenetics and the biological definition of Gene × Environment interactions. Child Development, 81, 4179. doi:10.1111/j.1467-8624.2009.01381.x
Melas, P. A., Wei, Y., Wong, C. C., Sjoholm, L. K., Aberg, E., Mill, J., … Lavbratt, C. (2013). Genetic and epigenetic associations of MAOA and NR3C1 with depression and childhood adversities. International Journal of Neuropsychopharmacology, 16, 15131528. doi:10.1017/S1461145713000102
Mulligan, C. J., D'Errico, N. C., Stees, J., & Hughes, D. A. (2012). Methylation changes at NR3C1 in newborns associate with maternal prenatal stress exposure and newborn birth weight. Epigenetics, 7, 853857. doi:10.4161/epi.21180
Muthén, L. K., & Muthén, B. O. (1998–2012). Mplus user's guide (6th ed.). Los Angeles: Author.
Na, K. S., Chang, H. S., Won, E., Han, K. M., Choi, S., Tae, W. S., … Ham, B. J. (2014). Association between glucocorticoid receptor methylation and hippocampal subfields in major depressive disorder. PLOS ONE, 9, e85425. doi:10.1371/journal.pone.0085425
Norman, R. E., Byambaa, M., De, R., Butchart, A., Scott, J., & Vos, T. (2012). The long-term health consequences of child physical abuse, emotional abuse, and neglect: A systematic review and meta-analysis. PLOS Medicine, 9, e1001349. doi:10.1371/journal.pmed.1001349
Oberlander, T. F., Weinberg, J., Papsdorf, M., Grunau, R., Misri, S., & Devlin, A. M. (2008). Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics, 3, 97106. doi:10.4161/epi.3.2.6034
Ostlund, B. D., Conradt, E., Crowell, S. E., Tyrka, A. R., Marsit, C. J., & Lester, B. M. (2016). Prenatal stress, fearfulness, and the epigenome: Exploratory analysis of sex differences in DNA methylation of the glucocorticoid receptor gene. Frontiers in Behavioral Neuroscience. Advance online publication. doi:10.3389/fnbeh.2016.00147
Palma-Gudiel, H., Cordova-Palomera, A., Leza, J. C., & Fananas, L. (2015). Glucocorticoid receptor gene (NR3C1) methylation processes as mediators of early adversity in stress-related disorders causality: A critical review. Neuroscience & Biobehavioral Reviews, 55, 520535. doi:10.1016/j.neubiorev.2015.05.016
Parade, S. H., Ridout, K. K., Seifer, R., Armstrong, D. A., Marsit, C. J., McWilliams, M. A., & Tyrka, A. R. (2016). Methylation of the glucocorticoid receptor gene promoter in preschoolers: Links with internalizing behavior problems. Child Development, 87, 8697. doi:10.1111/cdev.12484
Price, A. L., Patterson, N. J., Plenge, R. M., Weinblatt, M. E., Shadick, N. A., & Reich, D. (2006). Principal components analysis corrects for stratification in genome-wide association studies. Nature Genetics, 38, 904909. doi:10.1038/ng1847
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A., Bender, D., … Sham, P. C. (2007). PLINK: A tool set for whole-genome association and population-based linkage analyses. American Journal of Human Genetics, 81, 559575. doi:10.1086/519795
Roberts, S., Keers, R., Lester, K. J., Coleman, J. R., Breen, G., Arendt, K., … Havik, O. E. (2015). HPA axis related genes and response to psychological therapies: Genetics and epigenetics. Depression and Anxiety, 32, 861870. doi:10.1002/da.22430
Romens, S. E., McDonald, J., Svaren, J., & Pollak, S. D. (2015). Associations between early life stress and gene methylation in children. Child Development, 86, 303309. doi:10.1111/cdev.12270
Rutten, B. P. F., Vermetten, E., Vinkers, C. H., Ursini, G., Daskalakis, N. P., Pishva, E., … Kenis, G. (2017). Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder. Molecular Psychiatry. Advance online publication. doi:10.1038/mp.2017.120
Scheeringa, M. S., & Haslett, N. (2010). The reliability and criterion validity of the Diagnostic Infant and Preschool Assessment: A new diagnostic instrument for young children. Child Psychiatry and Human Development, 41, 299312. doi:10.1007/s10578-009-0169-2
Shonkoff, J. P., Boyce, W. T., & McEwen, B. S. (2009). Neuroscience, molecular biology, and the childhood roots of health disparities building a new framework for health promotion and disease prevention. Journal of the American Medical Association, 301, 22522259. doi:10.1001/jama.2009.754
Smith, A. K., Kilaru, V., Klengel, T., Mercer, K. B., Bradley, B., Conneely, K. N., … Binder, E. B. (2015). DNA extracted from saliva for methylation studies of psychiatric traits: Evidence tissue specificity and relatedness to brain. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 168, 3644. doi:10.1002/ajmg.b.32278
Stroud, L. R., Papandonatos, G. D., Rodriguez, D., McCallum, M., Salisbury, A. L., Phipps, M. G., … Marsit, C. (2014). Maternal smoking during pregnancy and infant stress response: Test of a prenatal programming hypothesis. Psychoneuroendocrinology, 48, 2940. doi:10.1016/j.psyneuen.2014.05.017
Szyf, M. (2013). The genome- and system-wide response of DNA methylation to early life adversity and its implication on mental health. Canadian Journal of Psychiatry, 58, 697704. doi:10.1177/070674371305801208
Turecki, G., & Meaney, M. J. (2016). Effects of the social environment and stress on glucocorticoid receptor gene methylation: A systematic review. Biological Psychiatry, 79, 8796. doi:10.1016/j.biopsych.2014.11.022
Tyrka, A. R., Burgers, D. E., Philip, N. S., Price, L. H., & Carpenter, L. L. (2013). The neurobiological correlates of childhood adversity and implications for treatment. Acta Psychiatrica Scandinavica, 128, 434447. doi:10.1111/acps.12143
Tyrka, A. R., Parade, S. H., Eslinger, N. M., Marsit, C. J., Lesseur, C., Armstrong, D. A., … Seifer, R. (2015). Methylation of exons 1D, 1F, and 1H of the glucocorticoid receptor gene promoter and exposure to adversity in pre-school aged children. Development and Psychopathology, 27, 577585. doi:10.1017/S0954579415000176
Tyrka, A. R., Parade, S. H., Welch, E. S., Ridout, K. K., Price, L. H., Marsit, C., … Carpenter, L. L. (2016). Methylation of the leukocyte glucocorticoid receptor gene promotor in adults: Associations with early adversity and depressive, anxiety and substance-use disorders. Translational Psychiatry, 6, e848. doi:10.1038/tp.2016.112
Tyrka, A. R., Price, L. H., Marsit, C., Walters, O. C., & Carpenter, L. L. (2012). Childhood adversity and epigenetic modulation of the leukocyte glucocorticoid receptor: Preliminary findings in healthy adults. PLOS ONE, 7, e30148. doi:10.1371/journal.pone.0030148
Tyrka, A. R., Ridout, K. K., & Parade, S. H. (2016). Childhood adversity and epigenetic regulation of glucocorticoid signaling genes: Associations in children and adults. Development and Psychopathology, 28, 13191331. doi:10.1017/S0954579416000870
US Department of Health and Human Services, Administration for Children and Families, Administration on Children, Youth and Families, Children's Bureau. (2017). Child Maltreatment 2015. Retrieved from
van der Knaap, L. J., Riese, H., Hudziak, J. J., Verbiest, M. M., Verhulst, F. C., Oldehinkel, A. J., … van Oort, F. V. (2014). Glucocorticoid receptor gene (NR3C1) methylation following stressful events between birth and adolescence. The TRAILS study. Translational Psychiatry, 4, e381. doi:10.1038/tp.2014.22
van der Knaap, L. J., van Oort, F. V., Verhulst, F. C., Oldehinkel, A. J., & Riese, H. (2015). Methylation of NR3C1 and SLC6A4 and internalizing problems. The TRAILS study. Journal of Affective Disorders, 180, 97103. doi:10.1016/j.jad.2015.03.056
Vinkers, C. H., Kalafateli, A. L., Rutten, B. P., Kas, M. J., Kaminsky, Z., Turner, J. D., & Boks, M. P. (2015). Traumatic stress and human DNA methylation: A critical review. Epigenomics, 7, 593608. doi:10.2217/epi.15.11
Vukojevic, V., Kolassa, I. T., Fastenrath, M., Gschwind, L., Spalek, K., Milnik, A., … de Quervaine, D. J. (2014). Epigenetic modification of the glucocorticoid receptor gene is linked to traumatic memory and post-traumatic stress disorder risk in genocide survivors. Journal of Neuroscience, 34, 1027410284. doi:10.1523/jneurosci.1526-14.2014
Weaver, I. C., Cervoni, N., Champagne, F. A., D'Alessio, A. C., Sharma, S., Seckl, J. R., … Meaney, M. J. (2004). Epigenetic programming by maternal behavior. Nature Neuroscience, 7, 847854. doi:10.1038/nn1276
Weder, N., Zhang, H., Jensen, K., Yang, B. Z., Simen, A., Jackowski, A., … O'Loughlin, K. (2014). Child abuse, depression, and methylation in genes involved with stress, neural plasticity, and brain circuitry. Journal of the American Academy of Child & Adolescent Psychiatry, 53, 417424.
Witzmann, S. R., Turner, J. D., Meriaux, S. B., Meijer, O. C., & Muller, C. P. (2012). Epigenetic regulation of the glucocorticoid receptor promoter 17 in adult rats. Epigenetics, 7, 12901301. doi:10.4161/epi.22363
Wong, C. C. Y., Caspi, A., Williams, B., Craig, I. W., Houts, R., Ambler, A., … Mill, J. (2010). A longitudinal study of epigenetic variation in twins. Epigenetics, 5, 516526. doi:10.4161/epi.5.6.12226
Yehuda, R., Daskalakis, N. P., Desarnaud, F., Makotkine, I., Lehrner, A. L., Koch, E., … Bierer, L. M. (2013). Epigenetic biomarkers as predictors and correlates of symptom improvement following psychotherapy in combat veterans with PTSD. Frontiers in Psychiatry, 4, 118.
Yehuda, R., Flory, J. D., Bierer, L. M., Henn-Haase, C., Lehrner, A., Desarnaud, F., … Meaney, M. J. (2015). Lower methylation of glucocorticoid receptor gene promoter 1 F in peripheral blood of veterans with posttraumatic stress disorder. Biological Psychiatry, 77, 356364. doi:10.1016/j.biopsych.2014.02.006


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed