Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: a link with the severity and type of trauma
Open accessAbstract
Childhood maltreatment, through epigenetic modification of the glucocorticoid receptor gene (NR3C1), influences the hypothalamic-pituitary-adrenal axis (HPA axis). We investigated whether childhood maltreatment and its severity were associated with increased methylation of the exon 1(F) NR3C1 promoter, in 101 borderline personality disorder (BPD) and 99 major depressive disorder (MDD) subjects with, respectively, a high and low rate of childhood maltreatment, and 15 MDD subjects with comorbid post-traumatic stress disorder (PTSD). Childhood sexual abuse, its severity and the number of type of maltreatments positively correlated with NR3C1 methylation (P=6.16 × 10(-8), 5.18 × 10(-7) and 1.25 × 10(-9), respectively). In BPD, repetition of abuses and sexual abuse with penetration correlated with a higher methylation percentage. Peripheral blood might therefore serve as a proxy for environmental effects on epigenetic processes. These findings suggest that early life events may permanently impact on the HPA axis though epigenetic modifications of the NR3C1. This is a mechanism by which childhood maltreatment may lead to adulthood psychopathology.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Higher NR3C1 exon 1F methylation levels are associated with increased severity of childhood trauma for physical abuse, physical neglect, emotional abuse, emotional neglect, and the total number of different types of childhood trauma.
“Similar associations of higher NR3C1 exon 1 F methylation levels with increased severity of childhood trauma were reported for physical abuse, physical neglect, emotional abuse and emotional neglect as well for the total number of different types of childhood trauma (Perroud et al., 2011)”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Perroud et al., 2011
The Results (‘Effect of childhood maltreatment on NR3C1 methylation’; page unavailable) report higher methylation with physical abuse, physical neglect, emotional abuse and emotional neglect in one sample, and with a greater number of maltreatment types. But the cited passages do not establish a severity gradient for each of those four individual types; the Results also report no association for physical abuse or emotional abuse or neglect in the BPD sample. (LLM, conf=0.88)
Experimental — accuracy not yet measuredChildhood neglect has been associated with increased methylation of NR3C1, corresponding with altered glucocorticoid signaling and reduced flexibility of HPA axis regulation.
“Childhood neglect has been associated with increased methylation of NR3C1, corresponding with altered glucocorticoid signaling and reduced flexibility of HPA axis regulation (65).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [65]
The Results (page unavailable) report higher NR3C1 methylation associated with childhood physical neglect and, in another sample, emotional neglect. The Discussion proposes that methylation could alter glucocorticoid feedback and HPA-axis activity, but presents this as a hypothesis; it does not establish altered signaling or measure reduced flexibility of HPA-axis regulation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSimilar glucocorticoid receptor hypermethylation has been demonstrated in hippocampal tissue and peripheral lymphocytes of humans maltreated in childhood.
“Similar GR hypermethylation was subsequently demonstrated in hippocampal tissue [52] and peripheral lymphocytes [53] of humans maltreated in childhood.”
From Biological embedding of childhood adversity: from physiological mechanisms to clinical implications (2017) · cites this paper as [53]
The Methods section reports that DNA was extracted from blood white cells, and the Results section finds higher NR3C1 methylation in adults who experienced childhood abuse. The paper does not report measuring isolated peripheral lymphocytes, so that tissue-specific wording is not fully supported. The hippocampal finding is attached to a different citation in the citing sentence. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn MDD, hypermethylation of the NR3C1 promoter impairs HPA-axis regulation following childhood trauma.
“hypermethylation of the NR3C1 promoter impairs hypothalamic-pituitary-adrenal (HPA)-axis regulation following childhood trauma”
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 [14]
The Discussion reports an association between childhood trauma and increased NR3C1 promoter methylation, and the study included participants with MDD. But it describes an effect on HPA-axis activity as a possible mechanism, not a demonstrated impairment of HPA-axis regulation in MDD. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn MDD, hypermethylation of NR3C1 promoter regions in individuals with childhood trauma is associated with reduced GR expression and dysregulation of the HPA axis.
“In MDD, hypermethylation of NR3C1 promoter regions in individuals with childhood trauma is associated with reduced GR expression and dysregulation of the HPA axis”
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 [14]
The Results (Effect of childhood maltreatment on NR3C1 methylation; page not provided) report higher promoter methylation with childhood maltreatment in a sample including people with MDD and BPD. The Discussion (page not provided) proposes that this methylation could disturb GR expression and HPA-axis feedback, but does not establish those effects in the MDD participants. The claim presents that proposed link as an observed association in MDD. (LLM, conf=0.89)
Experimental — accuracy not yet measured
At the level of NR3C1 there is consistent evidence on a positive correlation between childhood adversity and DNAm in Borderline PD and MDD and some clinical outcomes, and a negative correlation with anxiety and PTSD.
“at the level of NR3C1 there is consistent evidence on a positive correlation between CA and DNAm in Borderline PD and MDD and some clinical outcomes (Farrell et al., 2018; Martin-Blanco et al., 2014; Perroud et al., 2011; Radtke et al., 2015), and a negative correlation with anxiety and PTSD (Labonte, Azoulay, Yerko, Turecki, & Brunet, 2014; Schechter et al., 2015; Wang et al., 2017; Yehuda et al.”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Perroud et al., 2011
The Results (Effect of childhood maltreatment on NR3C1 methylation; page unavailable) report positive associations between childhood abuse or neglect and NR3C1 methylation in the studied BPD and MDD samples. The cited paper does not establish the added association with clinical outcomes: its Discussion (page unavailable) says BPD severity did not correlate with methylation. The negative associations with anxiety and PTSD are attached to other citations, not Perroud et al. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn a mixed mental disorder cohort, higher peripheral blood NR3C1 exon 1F methylation is significantly linked to experiences of sexual abuse, with a linear trend between the severity of sexual abuse and the extent of methylation.
“a significant link between higher peripheral blood NR3C1 exon 1 F methylation and experiences of sexual abuse, and a linear trend between the severity of sexual abuse and the extent of methylation have been reported (Perroud et al., 2011)”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Perroud et al., 2011
A substantial proportion of studies have focused on a limited number of stress-response genes, most notably FKBP5 and NR3C1.
“A substantial proportion of studies have focused on a limited number of stress-response genes, most notably FKBP5 and NR3C1 (55, 65, 83, 84, 121, 129).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [65]
In MDD, hypermethylation of BDNF promoters, especially exon IV, reduces BDNF expression and impairs neuroplasticity.
“In MDD, hypermethylation of BDNF promoters, especially exon IV, reduces BDNF expression and impairs neuroplasticity”
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 [14]
The Materials and methods section identifies the measured promoter as NR3C1 exon 1F, and the Discussion addresses NR3C1 methylation rather than BDNF. Searches for BDNF exon IV methylation and BDNF expression found no passage in our copy addressing the claimed reduction in expression or impaired neuroplasticity in MDD. (LLM, conf=0.76)
Experimental — accuracy not yet measuredChildhood maltreatment associates with an increased level of exon 1F methylation in peripheral blood lymphocytes.
“Perroud et al127,128 used peripheral blood lymphocytes to show that childhood maltreatment associates with an increased level of exon 1F methylation”
From Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function (2014) · cites this paper as [128]
The current data replicate previously demonstrated associations between child maltreatment and methylation of the GR gene.
“The fact that the current data replicate previously demonstrated associations between child maltreatment and methylation of the GR gene”
From Associations Between Early Life Stress and Gene Methylation in Children (2015) · cites this paper as Perroud et al., 2011
Similar associations between early adversity and GR NR3C1 methylation have been demonstrated in humans, including in brain tissue of deceased adults who committed suicide following child abuse, cord blood of infants with depressed mothers, white blood cells of adults with borderline personality disorder or major depressive disorder with child sexual abuse, whole blood of adults with bipolar and a,
“Similar associations between early adversity and GR NR3C1 methylation have recently been demonstrated in humans who likely experienced severe stress or trauma. These samples have included brain tissue of deceased human adults who had committed suicide following a history of child abuse (McGowan et al., 2009), cord blood of infants with depressed mothers (Oberlander et al., 2008), white blood cells”
From Associations Between Early Life Stress and Gene Methylation in Children (2015) · cites this paper as Perroud et al., 2011
The results are consistent with previous research in adult humans demonstrating an association between child abuse and methylation differences.
“our results are consistent with previous research in adult humans demonstrating an association between child abuse and methylation differences, despite differences in sample characteristics”
From Associations Between Early Life Stress and Gene Methylation in Children (2015) · cites this paper as Perroud et al., 2011
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
No citation lists for this paper
No citation lists for this paper yet — checked again daily.
References 51 · Cited by 516
Research works printed but not linked: 3
- De Bellis MD Baum AS Birmaher B Keshavan MS Eccard CH Boring AM A.E. Bennett Research Award. Developmental traumatology. Part I: Biological stress systems Biol Psychiatry 1999 45 1259 1270 10349032
- De Bellis MD Keshavan MS Clark DB Casey BJ Giedd JN Boring AM A.E. Bennett Research Award. Developmental traumatology. Part II: Brain development Biol Psychiatry 1999 45 1271 1284 10349033
- LaPrairie JL Heim C Nemeroff CB Neuroendocrine effects of early life traumaIn: Lanius RA, Vermetten E, Pain C (eds). The Impact of Early Life Trauma on Health and Disease. The Hidden Epidemic Cambridge University Press: Cambridge, UK 2010
- Authors
- Perroud, N., Paoloni-Giacobino, A., Prada, P., Olié, E., Salzmann, A., Nicastro, R., Guillaume, S., Mouthon, D., Stouder, C., Dieben, K., Huguelet, P., Courtet, P., & Malafosse, A.
- Affiliations
- University of Geneva (CH)
- University Hospital of Geneva (CH)
- Inserm (FR)
- Corresponding author
- Perroud, N
- Venue
- Translational Psychiatry
- Published
- 2011-12-13
- Volume
- 1
- Issue
- 12
- Pages
- e59-e59
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC3309499
- OpenAlex
- W1999272870
- Cited by
- 516
- References
- 51
- Citations by year
- 2026: 18 · 2025: 18 · 2024: 12 · 2023: 31 · 2022: 22 · 2021: 36 · 2020: 42 · 2019: 35 · 2018: 58 · 2017: 47 · 2016: 49 · 2015: 51 · 2014: 63 · 2013: 26 · 2012: 6
- FWCI
- 32.81
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (unspecified)
- Locations
- Translational Psychiatry (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- Agence Nationale de la Recherche
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (320030, 112084)
- Centre Hospitalier Régional Universitaire de Montpellier
- Topics
- Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- child abuse, glucocorticoid receptor, NR3C1, DNA methylation, promoter methylation, child sexual abuse, borderline personality disorder, major depressive disorder, post-traumatic stress disorder, hypothalamic-pituitary-adrenal axis, epigenetics, injury severity, peripheral blood biomarkers
- MeSH terms
- Adult, Child, Child Abuse, Sexual, Major Depressive Disorder, Depressive Disorder, Major, Female, Humans, Hypothalamo-Hypophyseal System, Male, Pituitary-Adrenal System, Receptors, Glucocorticoid, Severity of Illness Index, Stress Disorders, Post-Traumatic, DNA Methylation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
