Effects of the social environment and stress on glucocorticoid receptor gene methylation: A systematic review

Turecki, Gustavo; Meaney, Michael J.

doi:10.1016/j.biopsych.2014.11.022

Cited by 796Stress Responses and CortisolEpigenetics and DNA MethylationChild Abuse and Trauma

Effects of the social environment and stress on glucocorticoid receptor gene methylation: A systematic review

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Turecki, Gustavo, Meaney, Michael J.·2016·Biological Psychiatry

DOI 10.1016/j.biopsych.2014.11.022PMC PMC4466091

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Abstract

The early-life social environment can induce stable changes that influence neurodevelopment and mental health. Research focused on early-life adversity revealed that early-life experiences have a persistent impact on gene expression and behavior through epigenetic mechanisms. The hypothalamus-pituitary-adrenal axis is sensitive to changes in the early-life environment that associate with DNA methylation of a neuron-specific exon 17 promoter of the glucocorticoid receptor (GR) (Nr3c1). Since initial findings were published in 2004, numerous reports have investigated GR gene methylation in relationship to early-life experience, parental stress, and psychopathology. We conducted a systematic review of this growing literature, which identified 40 articles (13 animal and 27 human studies) published since 2004. The majority of these examined the GR exon variant 1F in humans or the GR17 in rats, and 89% of human studies and 70% of animal studies of early-life adversity reported increased methylation at this exon variant. All the studies investigating exon 1F/17 methylation in conditions of parental stress (one animal study and seven human studies) also reported increased methylation. Studies examining psychosocial stress and psychopathology had less consistent results, with 67% of animal studies reporting increased exon 17 methylation and 17% of human studies reporting increased exon 1F methylation. We found great consistency among studies investigating early-life adversity and the effect of parental stress, even if the precise phenotype and measures of social environment adversity varied among studies. These results are encouraging and warrant further investigation to better understand correlates and characteristics of these associations.

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ELS is associated with hypermethylation of NR3C1 in exon 1F, which is associated with downregulation of GR in brain and periphery.
“In the case of NR3C1, ELS is associated with hypermethylation particularly in exon 1F, which in turn is associated with downregulation of GR in the brain and periphery [80,81].”
From Trauma, PTSD, and the Developing Brain (2017) · cites this paper as [80]
The Results (Early-life adversity; page unavailable) report increased exon 1F methylation in 9 of 10 human studies of early-life adversity. The Introduction reports decreased GR1F expression in the hippocampus of suicide completers with childhood abuse histories. The Conclusion reports exon 1F methylation in peripheral cells but says its effect on GR expression there is likely, rather than establishing peripheral GR downregulation. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Hypermethylation of NR3C1 in individuals exposed to childhood adversity correlates with increased vulnerability to PTSD, depression, and suicide risk.
“hypermethylation of NR3C1 in individuals exposed to childhood adversity correlates with increased vulnerability to PTSD, depression, and suicide risk”
From The clinical use of epigenetics in psychiatry: a narrative review of epigenetic mechanisms, key candidate genes, and precision psychiatry (2025) · cites this paper as [2]
The Introduction and Conclusion report increased NR3C1 exon 1F methylation after childhood adversity, including in suicide completers with a history of abuse, and describe adversity-related vulnerability to depression or other mood disorders. They do not establish that hypermethylation predicts increased risk of all three outcomes. The Results (Psychological stress/Psychopathology) instead report mixed methylation findings across psychiatric conditions, including decreased exon 1F methylation in a PTSD study. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Klengel et al. and other investigators focusing on early childhood trauma effects and gene-by-early-life-environment interactions on methylation did not assess the contribution of parental experiences, particularly trauma exposure.
“Klengel et al. (38) and other investigators (51,52) focusing on early childhood trauma effects and the influence of the gene 3 early life environment interactions on methylation did not assess the contribution of parental experiences, particularly trauma exposure.”
From Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation (2016) · cites this paper as [51]
The Conclusion describes Klengel et al.’s finding on childhood maltreatment, FKBP5 genotype and methylation. The Results discuss parental stress in a separate group of studies, but do not establish that Klengel et al. or the other investigators named in the citing sentence failed to assess parental trauma exposure. (LLM, conf=0.78)
Experimental — accuracy not yet measured
Studies across animals and humans point to altered methylation and expression of GR (NR3C1) and FKBP5 following ELS.
“Studies across animals and humans point to altered methylation and expression of the glucocorticoid receptor (GR or NR3C1) and FKBP5, a GR chaperone protein which impedes GR signaling, following ELS [79–81].”
From Trauma, PTSD, and the Developing Brain (2017) · cites this paper as [80]
Other tissues such as cord blood, peripheral blood, buccal epithelial cells and placental tissues showed similar results regarding enhanced methylation of NR3C1 in association with early life adversity.
“Other tissues, such as cord blood, peripheral blood, buccal epithelial cells and placental tissues were also tested, and the majority of them showed similar results in regard to enhanced methylation of NR3C1 in association with early life adversity (138, 144).”
From Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma (2019) · cites this paper as [144]

Some overlap exists between MDD-associated differentially methylated regions in blood and the MDD-associated DMRs in the prefrontal cortex and other brain regions.
“Previous work indicates some overlap between MDD-associated differentially methylated regions (DMRs) in blood and the MDD-associated DMRs in the prefrontal cortex and other brain regions.82–85”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [84]
The Conclusion discusses possible coordinated methylation changes across peripheral and brain tissues after social adversity, but calls this reasoning speculative. The Results section describes studies of glucocorticoid-receptor methylation in blood and brain tissue; neither passage reports an overlap of MDD-associated DMRs between blood and the prefrontal cortex or other brain regions. Searches for that overlap and for shared depression-related methylation found no supporting passage in our copy. (LLM, conf=0.77)
Experimental — accuracy not yet measured
In human and rodent studies, changes to hippocampal circuitry are associated with early life adversity, suggesting an epigenetic mechanism for these changes and for major depressive disorder pathogenesis.
“Furthermore, in human and rodent studies, changes to hippocampal circuitry have been associated with early life adversity which suggests an epigenetic mechanism for these changes and MDD pathogenesis53, 54.”
From Dysregulation of adult hippocampal neuroplasticity in major depression: Pathogenesis and therapeutic implications (2022) · cites this paper as [53]
Combining GWAS with transcriptome data indicates that suicide-related genes are associated with inflammation, the HPA axis, GABA and glutamate neurotransmission, and neurogenesis.
“Combining GWASs with transcriptome data indicates that suicide-related genes are associated with inflammation, the hypothalamic-pituitary-adrenal (HPA) axis, γ-aminobutyric acid (GABA) and glutamate neurotransmission, and neurogenesis (51-56).”
From A brain-centric model of suicidal behavior (2020) · cites this paper as [55]
Chronic stress causes dendritic retraction in mPFC, dorsal hippocampus, and dorsomedial striatum but hypertrophy in BLA, vHPC, orbitofrontal cortex, and dorso-lateral striatum and no change in lateral or central subnuclei of the amygdala.
“Chronic stress causes dendritic retraction in mPFC, dorsal hippocampus, and dorsomedial striatum but hypertrophy in the BLA, vHPC, orbitofrontal cortex, and dorso-lateral striatum and no change in the lateral or central subnuclei of the amygdala (3,54,57–61).”
From Chronic Stress Remodels Synapses in an Amygdala Circuit-Specific Manner (2019) · cites this paper as [58]

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Authors: Turecki, G., & Meaney, M. J.
Affiliations: Douglas Mental Health University Institute (CA)
Corresponding author: Turecki, Gustavo
ORCID: Turecki, Gustavo
Meaney, Michael J.
Venue: Biological Psychiatry
Publisher: Elsevier BV
Published: 2016-01
Volume: 79
Issue: 2
Pages: 87-96
ISSN: 0006-3223 (ISSN-L)
DOI: 10.1016/j.biopsych.2014.11.022
PMC: PMC4466091
OpenAlex: W2039593919
Cited by: 796
References: 104
Citations by year: 2026: 34 · 2025: 49 · 2024: 66 · 2023: 57 · 2022: 51 · 2021: 69 · 2020: 125 · 2019: 68 · 2018: 78 · 2017: 113 · 2016: 54 · 2015: 27 · 2014: 1 · 2013: 1 · 2012: 2
FWCI: 5.29
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Biological Psychiatry (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Canadian Institute of Health Research (MOP93775, MOP11260, MOP119429, MOP119430)
National Institutes of Health (1R01DA033684-01)
Topics: Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
Keywords: glucocorticoid receptor, DNA methylation, childhood adversity, social environment, parental stress, psychosocial stress, psychopathology, hypothalamic-pituitary-adrenal axis, epigenetics, NR3C1, brain development
MeSH terms: Animals, Exons, Humans, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System, Promoter Regions, Genetic, Receptors, Glucocorticoid, Social Environment, Stress, Psychological, DNA Methylation, Epigenesis, Genetic, Rats

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Effects of the social environment and stress on glucocorticoid receptor gene methylation: A systematic review

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