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Methylation of the NR3C1 Gene and Behavior 
Rebecca Breitrick  

Department of Applied Psychophysiology, Saybrook University  
Published online: June 2025 

  © The Author(s) 2025 
  

Abstract 

Background: Methylation of the NR3C1 gene affects the glucocorticoid receptors, which are 

directly related to the stress response via the HPA axis. Exposure to various stressors can lead to 

methylation, causing significant changes in how a person interacts with their environment. 

Methods: A brief review was conducted of three research studies examining the interactions 

between the environment and the NR3C1 gene. 

Results: Research indicates an interplay between the type of stressor experienced, the degree of 

methylation, and an individual's level of resilience. NR3C1 methylation, which occurs in infants 

as a response to perinatal stressors, may be, at least temporarily, adaptive. In adolescents, NR3C1 

methylation is affected by exposure to stressors and trauma. 

Conclusion: Methylation of the NR3C1 gene can occur in response to the environment, and 

these changes impact a person’s behavior to varying degrees. 

Keywords: NR3C1, methylation, stressors 

 
 

 

 

 

 



  

Introduction 

The NR3C1 gene encodes the glucocorticoid receptors, which play an essential role in the 

stress response of the hypothalamic-pituitary-adrenal (HPA) axis. Methylation of the NR3C1 

gene can affect cortisol circulation and glucocorticoid sensitivity (Folger et al., 2019). 

Methylation of the NR3C1 gene and resulting changes in cortisol concentrations can also affect 

reward processing in the brain, potentially affecting personal resilience and “susceptibility to 

environmental exposures and may result in different neurodevelopmental and behavioral 

outcomes” (Xu et al., 2025, p.2). Research has indicated that NR3C1 methylation has occurred in 

response to perinatal stress, childhood abuse, and neglect, or other traumas (van der Knaap et al., 

2014). However, there is still much to learn about how and why these epigenetic changes occur 

and the effects they may have. 

NR3C1 Methylation, Childhood Maltreatment, and Reward Responsiveness 

A study completed by Xu et al. (2025) examined the relationship between childhood 

maltreatment, methylation of the NR3C1 gene, and reward responsiveness. The researchers 

hypothesized that "the Epi X E (Epigenome X Environment) interaction might work on RewP 

(reward positivity), gain-related delta and self-reported RR (reward responsiveness) but not loss-

related theta" (p. 3). Their hypothesis asserted that these interactions would relate to experiences 

of depression and anxiety and have a significant effect on the experience of anhedonia, a 

common symptom of depression defined as the inability to experience pleasure (Xu et al., 2025).   

 Participants in the study included 192 young adults of both genders, of Han descent, and 

with no diagnosed developmental, neurological, or significant physical disorders. The study 

included a baseline assessment and a follow-up assessment one year following. At baseline, 

participants completed the Childhood Trauma Questionnaire, which assessed five types of 



  

maltreatment (sexual, emotional, or physical abuse and emotional or physical neglect). Cheek 

swabs were used to analyze genomic DNA, focused on methylation in the NR3C1 region. EEG 

data was collected while participants completed a computerized reward task, which included 40 

gain and 40 loss trials. Participants completed a self-reported RR scale to assess motivation and 

approach behaviors, and The Beck Depression Inventory (BDI) and Self-Rating Anxiety Scale 

(SAS) were used to assess depression and anxiety. At the one-year follow-up, the BDI and SAS 

were repeated (Xu et al., 2025). 

 The results demonstrated a negative association between severity and number of 

exposures to childhood maltreatment and RewP in individuals with increased NR3C1 

methylation but a positive association in individuals with "blunted" methylation (Xu et al., p. 

10). The Epi X E effect was driven by emotional abuse and neglect but not by other types of 

maltreatment. Interaction effects were linked to anhedonia but not to gain-related delta, loss-

related theta, or self-reported RR. The research did not demonstrate a linkage to total depression 

or anxiety ratings (Xu et al., 2025).  

 The authors concluded that the results of the study demonstrated some evidence for the 

Epi X E model, noting that the effects of maltreatment seemed to be affected by type, severity, 

amount of maltreatment, and the amount of NR3C1 methylation. The results also demonstrated 

support for the "goodness-of-fit" model, which proposes that "some individuals might develop 

resilience when their characteristics can successfully deal with the stress; otherwise, the stress 

might defeat them and lead to dysfunction" (Xu et al., 2025, p. 10). 

NR3C1 Methylation and Early Development 

 Folger et al. (2019) reported on a pilot study completed with mother-child dyads 

participating in an early intervention home visit program. Their hypothesis asserted that “the 



  

mean NR3C1 DNAm (DNA methylation) across 10 CpG (cytosine-guanine dinucleotides) sites 

in the promotor region would be significantly associated with subsequent infant social-emotional 

functioning” (Folger et al., 2019, p. 2).  

 The participants of this study included 53 adult mothers who were pregnant during the 

first visit of the study and then completed a second visit one month post-partum. Follow-up 

assessment of some participating infants occurred at 6 and 18 months. There was a high drop-out 

rate due to a variety of factors. At the first visit, The Edinburgh Postnatal Depression Scale 

(EPDS) screened for major or minor depression in the mother, and the Interpersonal Support 

Evaluation List (ISEL-40) measured the mother’s perceived interpersonal support. Multiple 

cheek swabs were taken from the infants at the second visit to look for methylation in the 

NR3C1 region. The Ages and Stages Questionnaire: Social-Emotional (ASQ:SE) was used 

during the two follow-up visits to assess social-emotional function. (Folger et al., 2019).  

 The percentage of NR3C1 methylation and the ASQ:SE scores at the 6-month mark. 

Lower ASQ:SE scores indicated higher functioning. At the 18-month mark, there continued to be 

a negative correlation, although it was no longer statistically significant. Further analysis showed 

that specific CpG sites seemed to have the strongest associations with the ASQ:SE scores (Folger 

et al., 2019). Folger et al. (2019) wrote this about their results: “Increased DNAm may reflect a 

compensatory response to prenatal adversity among some infants who have parents enrolled in 

an HV (home visit) program" (p. 7). They pointed out that while the increase in methylation may 

have served some protective functions, a larger study would be warranted to clarify this 

phenomenon. They also referred to another study that showed that, while methylation may be 

protective in one area of development, other areas may be adversely affected. (Folger et al., 

2019).  



  

 

NR3C1 Methylation and Stressful Events over Childhood and Adolescence 

 A study reported by van der Knaap et al. (2014) used data collected through the Tracking 

Adolescents’ Individual Lives Survey (TRAILS) to examine the connection between NR3C1 

methylation in adolescence and previous life stressors. The researchers hypothesized that 

“perinatal stress, many SLEs (stressful life events), and traumatic youth experiences would relate 

to higher NR3C1 methylation in adolescence" (van der Knaap et al., 2014, p.2).   

 The TRAILS study followed over 2,000 male and female Dutch youth from pre-

adolescence into adulthood, collecting data every two or three years starting around age 11. Van 

der Knaap et al. (2014) focused their study on 468 participants who had, around age 16, 

undergone blood work to analyze DNA. This group of participants, admittedly, included a 

disproportionate (66%) percentage of “high-risk adolescents” who were deemed more likely to 

experience mental health issues due to increased risk factors (van der Knaap et al., 2014).   

Interviews with parents and records review were used to determine exposure to perinatal 

stress. Researchers gathered information about stressful life events and traumatic experiences via 

parental interviews or self-reports. Stressful life events included things like parental divorce, 

death or illness of family or friends, lack of friends, hospitalization, etc. In contrast, traumatic 

events included sexual assault/abuse, physical abuse, life-threatening experiences, etc.  (van der 

Knaap et al., 2014). 

Data analysis showed an association between stressful life events during adolescence, 

traumas, and higher methylation. However, results of this research did not show an association 

between methylation of NR3C1 and perinatal or childhood stress (van der Knaap et al., 2014). 

The authors proposed that because these results conflict with past research demonstrating 



  

NR3C1 methylation associated with perinatal stress, further research was warranted to see if 

some epigenetic changes are short-term and reversible (van der Knaap et al., 2014). Van der 

Knaap et al. (2014) acknowledged that it would have been helpful if DNA was analyzed more 

than once to see if methylation changed over time and to help determine causation. 

Conclusion 

 There is much to learn about epigenetics and the relationship between genes and the 

environment. Research into NR3C1 has shown that methylation can occur in response to the 

environment, and these changes can significantly impact how an individual continues to react to 

the environment. The research also demonstrates a need for further work to elucidate the specific 

mechanisms and effects. 

  

 

 

 

 

 

 

 

 

 

 

 

 



  

References 

Folger, A. T., Ding, L., Ji, H., Yolton, K., Ammerman, R. T., Van Ginkel, J., B., & Bowers, K. 

(2019). Neonatal NR3C1 Methylation and Social-Emotional Development at 6 and 18 

Months of Age. Frontiers in Behavioral Neuroscience, 13, 

14. https://10.3389/fnbeh.2019.00014 

van der Knaap, L. J., Riese, H., Hudziak, J. J., Verbiest, M. M. P. J., Verhulst, F. C., Oldehinkel, 

A. J., & van Oort, F. V. A. (2014). Glucocorticoid receptor gene (NR3C1) methylation 

following stressful events between birth and adolescence. The TRAILS 

study. Translational Psychiatry, 4(4), e381. https://10.1038/tp.2014.22 

Xu, Y., Yang, S., & Cao, C. (2025). Glucocorticoid receptor gene (NR3C1) methylation, 

childhood maltreatment, multilevel reward responsiveness, and depressive and anxiety 

symptoms: A neuroimaging epigenetic study. NeuroImage (Orlando, Fla.), 306, 

121003. https://10.1016/j.neuroimage.2025.121003 

https://10.0.13.61/fnbeh.2019.00014
https://10.0.4.14/tp.2014.22
https://10.0.3.248/j.neuroimage.2025.121003

