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Cited by 299Child Abuse and TraumaEpigenetics and DNA MethylationStress Responses and Cortisol

Associations Between Early Life Stress and Gene Methylation in Children

Open access
Romens, Sarah E, McDonald, Jennifer, Svaren, John, Pollak, Seth D·2015·Child Development
DOI 10.1111/cdev.12270PMC PMC4305348
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Abstract

Children exposed to extreme stress are at heightened risk for developing mental and physical disorders. However, little is known about mechanisms underlying these associations in humans. An emerging insight is that children's social environments change gene expression, which contributes to biological vulnerabilities for behavioral problems. Epigenetic changes in the glucocorticoid receptor gene, a critical component of stress regulation, were examined in whole blood from 56 children aged 11–14 years. Children exposed to physical maltreatment had greater methylation within exon 1F in the NR3C1 promoter region of the gene compared to nonmaltreated children, including the putative NGFI-A (nerve growth factor) binding site. These results highlight molecular mechanisms linking childhood stress with biological changes that may lead to mental and physical disorders.

AI snapshot

Written from the paper’s full text.

TL;DR

Children with verified physical maltreatment showed greater methylation within exon 1F of the NR3C1 glucocorticoid receptor promoter compared with nonmaltreated children, including at a putative NGFI-A binding site. The findings suggest a molecular pathway linking early life stress to altered stress regulation, though the study cannot establish causality or brain-level effects.

Key findings

  • In 56 children aged 11–14, maltreated children (n = 18) had greater methylation than nonmaltreated children (n = 38) depending on CpG site, F(6.59, 355.68) = 2.46, p = .02.
  • Maltreated children had more methylation at CpG site 3, t(54) = −2.91, p = .01, d = 0.79; CpG site 6, t(19.77) = −2.14, p = .05, d = 0.96; and CpG site 7, t(23.37) = −2.18, p = .05, d = 0.90. CpG site 3 is within the putative NGFI-A binding site.
  • In a socioeconomic-status-matched subset (17 maltreated, 17 nonmaltreated), the pattern remained: methylation varied by CpG site, F(5.33, 170.42) = 2.32, p = .04, with more methylation at CpG site 3, t(32) = −3.13, p = .004, d = 1.10; site 5, t(32) = −2.68, p = .01, d = 0.95; and site 6, t(32) = −2.11, p = .04, d = 0.75, and less methylation at CpG site 2, t(32) = 2.05, p = .048, d = 0.72.
  • Maltreated children had lower socioeconomic status (M = 32.65, SD = 13.59) than nonmaltreated children (M = 47.96, SD = 9.74), t(23.86) = 4.18, p < .001, d = 1.71.

Methods

  • Participants were 56 children (30 males, 26 females) aged 11–14 (Mage = 12.11, SDage = 0.78); 18 had reports of physical maltreatment and 38 had no Child Protective Services records.
  • Genomic DNA was extracted from whole blood, bisulfite-converted, PCR-amplified for a 150-bp region of NR3C1 exon 1F, and analyzed by bisulfite pyrosequencing for percentage methylation at 13 CpG sites, with two technical replicates.
  • Analyses included independent-samples t tests and Pearson chi-square tests for demographic differences, a 2 (maltreatment group) × 13 (CpG site) mixed ANOVA with Greenhouse–Geisser correction, planned t tests at each CpG site, and a repeated mixed ANOVA in an SES-matched subset.

Limitations

  • The paper states that the study cannot directly address causality or cellular processes occurring within the brains of living children.
  • The paper states that it did not examine gene expression, protein synthesis, or behavior related to GR methylation, and that leukocyte methylation may not have the same function as central methylation in the brain.
  • The paper states that it could not control for all possible confounding variables that co-occur with child abuse, and calls for further research measuring additional background and environmental factors; the text also makes evident that the sample was small and cross-sectional.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1111/cdev.12270

Cites

30 of 30 references verified0 citation errors · 0 not checkable

Statistics

10 tests recomputed · 0 with the reported and recomputed p on opposite sides of .05

Claims the paper makes

0 of 29 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Children with histories of physical maltreatment had greater methylation within exon 1F of the NR3C1 promoter region compared to nonmaltreated children.

    “Children exposed to physical maltreatment had greater methylation within exon 1F in the NR3C1 promoter region of the gene compared to nonmaltreated children, including the putative NGFI-A (nerve growth factor) binding site.”
    • Also stated in: § Discussion · plain
      “The data from this study revealed that children who experienced physical maltreatment displayed a specific epigenetic change to the glucocorticoid receptor gene. Specifically, these children had more methylation of several sites within exon 1F of the NR3C1 promoter region.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Reports in Child Protective Services records accurately indicate that a child experienced physical maltreatment.
  • Findingown data

    Children with histories of maltreatment had families with lower socioeconomic status than children without a history of maltreatment.

    “children with histories of maltreatment had families with lower SES (MSES = 32.65, SDSES = 13.59) compared to children with no maltreatment history (MSES = 47.96, SDSES = 9.74), t(23.86) = 4.18, p < .001, d = 1.71.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Reports in Child Protective Services records accurately indicate that a child experienced physical maltreatment.
  • Findingown data

    In a socioeconomic-status-matched subset, children with histories of maltreatment had greater methylation at CpG site 3 compared to nonmaltreated children.

    “Children with histories of maltreatment had more methylation at CpG site 3, t(32) = −3.13, p = .004, d = 1.10”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Reports in Child Protective Services records accurately indicate that a child experienced physical maltreatment.
  • Findingown data

    In a socioeconomic-status-matched subset, children with histories of maltreatment had less methylation at CpG site 2 compared to nonmaltreated children.

    “children with histories of maltreatment had less methylation at CpG site 2, t(32) = 2.05, p = .048, d = 0.72”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Reports in Child Protective Services records accurately indicate that a child experienced physical maltreatment.
  • Findingown data

    Children with histories of maltreatment had greater methylation at CpG site 6 compared to nonmaltreated children.

    “CpG site 6, t(19.77) = −2.14, p = .05, d = 0.96”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Reports in Child Protective Services records accurately indicate that a child experienced physical maltreatment.
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 14
  • May combine two claims. 11

  • The quote only partly states this claim.

    Findingown data

    The greater methylation in maltreated children included CpG site 3, which is part of the putative NGFI-A binding site.

    “children with histories of maltreatment had more methylation at CpG site 3, t(54) = −2.91, p = .01, d = 0.79”
    • Also stated in: § Discussion · plain
      “Of particular importance, the differences that we observed include a precise part of the gene, CpG site 3, which is part of the putative NGFI-A binding site.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Reports in Child Protective Services records accurately indicate that a child experienced physical maltreatment.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationnone given

    The present study cannot directly address causality or the cellular processes occurring within the brains of living children.

    “However, the present study cannot directly address causality or the cellular processes occurring within the brains of living children.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Adversity-related increases in methylation in this region are associated with decreased gene expression in human postmortem brain tissue and increased physiological stress responding in infants.

    “adversity-related increases in methylation in this region are associated with decreased gene expression in human postmortem brain tissue (McGowan et al., 2009) and increased physiological stress responding in infants (Oberlander et al., 2008).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites McGowan et al., 2009 source

      Not checked in the free run.

    • cites Oberlander et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Individuals with maltreatment histories are reported to have elevated inflammation, elevated production of antibodies, compromised immune functioning, and poorer health compared to nonmaltreated individuals.

    “individuals with maltreatment histories are reported to have elevated inflammation, elevated production of antibodies, compromised immune functioning, and poorer health compared to nonmaltreated individuals (Danese et al., 2008; Shirtcliff, Coe, & Pollak, 2009).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Danese et al., 2008 source

      Not checked in the free run.

    • cites Shirtcliff, Coe, & Pollak, 2009

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The findings open a window into the molecular mechanisms linking early stress exposure to the emergence of psychopathology.

    “also opens a window into the molecular mechanisms linking early stress exposure to the emergence of psychopathology.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: GR methylation is an index of gene activation.

  • May combine two claims.

    Interpretationreasoning

    The fact that data in living human children parallels findings in rodents, and that rodent experiments directly address potential confounding variables, militates against alternative hypotheses.

    “The fact that the data in living human children parallels findings in rodents, and that the rodent experiments directly address potential confounding variables (e.g., predisposing genetic factors, nutrition differences, general environmental stimulation, health) militates against alternative hypotheses.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    HPA axis dysregulation has been implicated in the etiology of a range of psychological disorders.

    “This dysregulation has been implicated in the etiology of a range of psychological disorders (Heim & Nemeroff, 2001; Heim, Newport, Mletzko, Miller, & Nemeroff, 2008).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Heim & Nemeroff, 2001 source

      Not checked in the free run.

    • cites Heim et al., 2008 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Methylation patterns in leukocytes may not have the same function as central methylation in the brain.

    “methylation patterns in leukocytes (blood) may not have the same function as central methylation in the brain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    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”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites McGowan et al., 2009 source

      Not checked in the free run.

    • cites Oberlander et al., 2008 source

      Not checked in the free run.

    • cites Perroud et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Subsequent decreases in NGFI-A binding lead to decreased levels of GRs in the hippocampus, resulting in impaired regulation of stress response systems and behavior.

    “Subsequent decreases in NGFI-A binding then leads to decreased levels of GRs in the hippocampus, which results in impaired regulation of stress response systems and behavior (Weaver et al., 2004; Weaver et al., 2005).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Weaver et al., 2004 source

      Not checked in the free run.

    • cites Weaver et al., 2005 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In mammals, perceived physical and social stress produces changes in physiological stress regulation systems that enhance threat detection, increase available energy for intense physical activity, and heighten immune responses involved in wound repair.

    “In mammals, perceived physical and social stress produces changes in physiological stress regulation systems that enhance threat detection, increase available energy for intense physical activity (e.g., fight or flight), and heighten immune responses involved in wound repair (Hostinar & Gunnar, 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hostinar & Gunnar, 2013

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    Disruption of healthy stress regulatory systems might account for issues frequently observed in populations of maltreated individuals, including behavior regulation problems in early childhood, increased incidence of mental and substance-related disorders in emerging adulthood, and high rates of physical health problems later in life.

    “For example, disruption of healthy stress regulatory systems might account for issues frequently observed in populations of maltreated individuals, including behavior regulation problems in early childhood, increased incidence of mental and substance-related disorders in emerging adulthood, and high rates of physical health problems later in life.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    The rodent models of alterations in GR methylation hold great promise for understanding specific mechanisms linking child maltreatment to development of psychopathology.

    “The rodent models of alterations in GR methylation hold great promise for understanding specific mechanisms linking child maltreatment to development of psychopathology.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: GR methylation is an index of gene activation.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    When Levene's test indicated unequal variance between groups, the degrees of freedom were corrected using the Welch-Satterthwaite approach.

    “When Levene's test for equality of variance indicated unequal variance between groups, we corrected the degrees of freedom using the Welch–Satterthwaite approach.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    These findings have not been tested in or extended to living human children who have recently and definitively endured abusive parenting.

    “However, these findings have not been tested in or extended to living human children who have recently and definitively endured abusive parenting.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    All experimental procedures were approved by the appropriate Institutional Review Board and carried out in accordance with the World Medical Association Declaration of Helsinki.

    “All experimental procedures were approved by the appropriate Institutional Review Board and were carried out in accordance with the provisions of the World Medical Association Declaration of Helsinki.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Increased methylation would likely contribute to fewer GRs in the brain and blood, thereby impairing the physiology of stress regulation.

    “This increased methylation would likely contribute to fewer GRs in the brain and blood, thereby impairing the physiology of stress regulation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: GR methylation is an index of gene activation.

  • May combine two claims.

    Interpretationcitation

    Experiences in daily life can effectively turn on and off genes, leading to cascades of downstream changes in biology and behavior.

    “In this manner, experiences in daily life can effectively “turn on” and “turn off” genes, leading to cascades of downstream changes in biology and behavior.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: GR methylation is an index of gene activation.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cortisol binds with GR receptors in the hippocampus to regulate the HPA axis and inhibit further release of CRH.

    “Cortisol binds with glucocorticoid (GR) receptors in the hippocampus to regulate the HPA axis and inhibit further release of CRH.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lupien et al., 2009 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The Greenhouse-Geisser correction was applied to adjust for heterogeneity of covariance.

    “The Greenhouse–Geisser correction was applied to adjust for heterogeneity of covariance.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cortisol released in response to stress binds with GR receptors at the cellular level to regulate the immune system.

    “Similarly, cortisol released in response to stress binds with GR receptors at the cellular level to regulate the immune system (Lupien, McEwen, Gunnar, & Heim, 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lupien et al., 2009 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Two technical replicates of bisulfite pyrosequencing provided estimates of the percentage methylation of each CpG island.

    “Two technical replicates of bisulfite pyrosequencing provided estimates of the percentage methylation of each CpG island (Dupont, Tost, Jammes, & Gut, 2004).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dupont et al., 2004 source

      Not checked in the free run.

22 of 22

  • The paper relies on this without support.

    Few targeted and effective psychological interventions have been designed for maltreated children because of a lack of knowledge about specific biological systems amenable to change.

    “Yet few targeted and effective psychological interventions have been designed for these children because we lack knowledge about specific biological systems amenable to change.”

  • The paper relies on this without support.

    GR methylation is an index of gene activation.

    “GR methylation is an index of gene activation.”

  • The paper relies on this without support.

    Reports in Child Protective Services records accurately indicate that a child experienced physical maltreatment.

    “These data indicated that 38 participants had no CPS records and 18 participants had reports of physical maltreatment.”
3 of 3

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?

Statistics that don’t add up

Each reported p-value recomputed from its test statistic and degrees of freedom.

  • Inconsistent p-value: t(23.37) = −2.18, p = .05

    Minor

    The paper reports p = .05 here; recomputing from the test statistic and its degrees of freedom gives p = .040 (two-tailed). The check cannot tell whether the statistic or the p-value is the misprint.

    Reported p = .05 · recomputed p = .040

1 of 1

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Doesn’t add upt(23.37) = -2.18reported p = .05 · recomputed p = .040

    “t(23.37) = −2.18, p = .05”

  • Consistentt(23.86) = 4.18reported p < .001 · recomputed p < .001

    “t(23.86) = 4.18, p < .001”

  • ConsistentF(6.59, 355.68) = 2.46reported p = .02 · recomputed p = .018

    “F(6.59, 355.68) = 2.46, p = .02”

  • Consistentt(54) = -2.91reported p = .01 · recomputed p = .005

    “t(54) = −2.91, p = .01”

  • Consistentt(19.77) = -2.14reported p = .05 · recomputed p = .045

    “t(19.77) = −2.14, p = .05”

  • ConsistentF(5.33, 170.42) = 2.32reported p = .04 · recomputed p = .045

    “F(5.33, 170.42) = 2.32, p = .04”

  • Consistentt(32) = -3.13reported p = .004 · recomputed p = .004

    “t(32) = −3.13, p = .004”

  • Consistentt(32) = -2.68reported p = .01 · recomputed p = .012

    “t(32) = −2.68, p = .01”

  • Consistentt(32) = -2.11reported p = .04 · recomputed p = .043

    “t(32) = −2.11, p = .04”

  • Consistentt(32) = 2.05reported p = .048 · recomputed p = .049

    “t(32) = 2.05, p = .048”

10 of 10

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Self-check results appear here once an independent check has confirmed them.

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 1

  1. U.S. Department of Health and Human Services, 2011, Child maltreatment

Cited by

Sorted by citations

Related

Authors
Romens, S. E., McDonald, J., Svaren, J., & Pollak, S. D.
Affiliations
University of Wisconsin–Madison (US)
Corresponding author
Pollak, Seth D
ORCID
Venue
Child Development
Publisher
Oxford University Press (OUP)
Published
2015-01-01
Volume
86
Issue
1
Pages
303-309
ISSN
  • 0009-3920 (ISSN-L)
  • 1467-8624
DOI
10.1111/cdev.12270
PMC
PMC4305348
OpenAlex
W2157255715
Semantic Scholar
b207bb46205bd7d00b6c0879c15672efb6822828
Cited by
299
References
30
Citations by year
2026: 2 · 2025: 20 · 2024: 12 · 2023: 18 · 2022: 9 · 2021: 29 · 2020: 46 · 2019: 32 · 2018: 30 · 2017: 45 · 2016: 25 · 2015: 21 · 2014: 10
FWCI
39.73
Type
journal article
Language
en
Open access
Licence
Locations
  • Child Development (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (MH61285)
  • National Institute of Mental Health (R01MH61285, F31MH088111)
  • Early Experience, Stress and Neurobehavioral Development Center (P50MH078105)
  • Waisman Center
  • University of Wisconsin
  • National Institute of Child Health and Human Development (P30HD03352)
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
early life stress, DNA methylation, glucocorticoid receptor, NR3C1, physical abuse, childhood abuse, epigenetics, promoter methylation, children, stress regulation, biological vulnerability
MeSH terms
Adolescent, Child, Child Abuse, Female, Humans, Male, Receptors, Glucocorticoid, Repressor Proteins, Stress, Psychological, DNA Methylation, Epigenesis, Genetic

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