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Cited by 56Posttraumatic Stress Disorder ResearchEpigenetics and DNA MethylationChild Abuse and Trauma

DNA methylation of NR3C1 and FKBP5 is associated with posttraumatic stress disorder, posttraumatic growth, and resilience.

Open access
Miller, Olivia, Shakespeare-Finch, Jane, Bruenig, Dagmar, Mehta, Divya·2020·Psychological Trauma: Theory, Research, Practice, and Policy
DOI 10.1037/tra0000574
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Abstract

OBJECTIVE Understandings of the biological mechanisms underpinning posttrauma responses are limited. This pilot study aimed to expand research in this area by examining the relationship between DNA methylation of stress genes nuclear receptor subfamily 3 group C member 1 (NR3C1) and FK06 binding protein 5 (FKBP5) with an array of posttrauma responses of posttraumatic stress disorder (PTSD) symptom severity, posttraumatic growth (PTG), and resilience. METHOD First-year paramedicine students (N = 47) completed self-report measures of PTSD symptom severity, PTG, and resilience and provided a saliva sample for methylation analysis. Surrogate variable analyses identified covariates after which generalized regression models were performed to identify genomic sites significantly associated with PTSD symptom severity, PTG, or resilience. RESULTS Methylation of different FKBP5 and NR3C1 sites was significantly associated with PTSD symptom severity, PTG, and resilience. Methylation in FKBP5 site cg07485685 was a predictor of both PTSD symptom severity and resilience in opposite directions. CONCLUSIONS This is the first study investigating methylation changes in PTG, and overall the results suggest that NR3C1 and FKBP5 methylation is associated with both positive and negative posttrauma responses. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Integrity signals

Registry

Crossref · 10.1037/tra0000574

Cites

39 of 41 references verified2 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

6 of 33 cited sources checked · 1 supported · 2 flagged · accuracy not yet measured

  • Interpretationown data

    This finding tends to contradict previous findings where FKBP5 methylation has been associated with PTSD.

    “This finding tends to contradict previous findings where FKBP5 methylation has been associated with PTSD (e.g., Yehuda et al., 2016;Methal et al., 2019).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Yehuda et al., 2016 source

      The Results section on Holocaust survivors and F0 comparison subjects (page unavailable) reports no significant main effect of PTSD diagnosis on FKBP5 intron 7 methylation. It attributes the observed methylation difference primarily to Holocaust exposure, rather than PTSD diagnosis. (LLM, conf=0.86)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites Methal et al., 2019

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Findingown data

    Methylation of NR3C1 and FKBP5 were only associated with low levels of PTG and not heightened PTG.

    “It is important to note that methylation of NR3C1 and FKBP5 were only associated with low levels of PTG and not heightened PTG.”
    Quote in the paperSubstantial claim
  • Findingown data

    Methylation of promotor-associated region cg03906910 of NR3C1 was significantly associated with heightened PTSD symptom severity.

    “Results demonstrated that methylation of promotor-associated region cg03906910 of NR3C1 was significantly associated with heightened PTSD symptom severity.”
    Quote in the paperSubstantial claim
  • Findingown data

    Resilience was significantly associated with methylation of different regions of both NR3C1 (5 sites) and FKBP5 (2 sites).

    “Resilience was significantly associated with methylation of different regions of both NR3C1 (5 sites) and FKBP5 (2 sites).”
    Quote in the paperSubstantial claim
  • Findingown data

    For resilience, a total of 7 CpG sites (2 in FKBP5 and 5 in NR3C1) were significantly associated with resilience scores (p<0.05).

    “For resilience (Table 3), a total of 7 CpG sites (2 in FKBP5 and 5 in NR3C1) were significantly associated with resilience scores (p<0.05).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 21
  • May combine two claims. 12

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

    Study design and conductcitation

    SWAN normalisation removed technical differences between MINFI package Infinium I and Infinium II probes.

    “SWAN normalisation removed technical differences between MINFI package Infinium I and Infinium II probes (Maksimovic, Gordon & Oshlack, 2012;Pidsley et al., 2013).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Maksimovic et al., 2012 source

      The Background says SWAN is available in the minfi package and substantially reduces differences between Infinium I and II probe distributions. The Results section, “SWAN makes Infinium I and II β value distributions more similar,” reports smaller but nonzero differences after normalization, so “removed” overstates the finding. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Pidsley et al., 2013 source

      In Results and discussion, “Qualitative observations on preprocessing and normalization” (page unavailable), the paper describes SWAN’s segmented quantile-normalization scheme as counterproductive relative to dasen. Its “Preprocessing and normalization method design” section attributes reduction of Type I/II background differences to other methods, not SWAN. The paper therefore does not report that SWAN removed those technical differences. (LLM, conf=0.76)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Surrogate variable analyses revealed 4 significant SVA vectors that were used as covariates in the model to correct for technical artefacts and hidden confounds.

    “Surrogate variable analyses (SVAs) revealed 4 significant SVA vectors that were used as covariates in the model to correct for technical artefacts and hidden confounds (Leek & Storey, 2007).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Leek & Storey, 2007 source

      The Results section (“Surrogate Variables”; page not available) says SVA identifies significant vectors and incorporates the resulting surrogate variables as covariates in subsequent analyses. The paper supports using them to account for unmodeled variation, but it does not report that this citing analysis found four significant vectors or used four in its model. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    HPA-axis dysregulation is related to PTSD after trauma.

    “It has been proposed that HPA-axis dysregulation is related to PTSD after trauma (Hing et al., 2014;Yehuda, 2009); and by the same reasoning, it can be predicted that well-being after trauma (e.g., PTG and resilience) is related to healthy HPA-axis functioning.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Hing et al., 2014 source
    • cites Yehuda, 2009 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Healthy HPA-axis function indicated by a diurnal cortisol slope has been significantly associated with heightened PTG in breast cancer survivors.

    “For example, healthy HPA-axis function indicated by a diurnal cortisol slope has been significantly associated with heightened PTG in breast cancer survivors (Diaz, Aldridge-Gerry & Spiegel, 2014).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Diaz et al., 2014 source

      The Results report that higher posttraumatic growth scores were significantly associated with more negative, normal diurnal cortisol slopes. The Discussion specifies that the participants had metastatic breast cancer; the claim broadens this finding to breast cancer survivors generally. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Methylation of 3 NR3C1 sites was significantly associated with reduced resilience, while methylation of 2 other NR3C1 sites was significantly associated with heightened resilience.

    “Methylation of 3 NR3C1 sites was significantly associated with reduced resilience, while methylation of 2 other NR3C1 sites was significantly associated with heightened resilience.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    DNA methylation at FKBP5 site cg07485685 was associated with reduced PTSD symptom severity and increased resilience.

    “such that DNA methylation at the CpG site was associated with reduced PTSD symptom severity and increased resilience”
    • Also stated in: § Discussion · plain
      “That is, methylation of this site was significantly associated with reduced PTSD symptom severity and heightened resilience.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Hypomethylation of a promotor-associated NR3C1 region and hypermethylation of a non-promotor NR3C1 region were significantly associated with reduced PTG.

    “Hypomethylation of a promotor-associated NR3C1 region and hypermethylation of a non-promotor NR3C1 region were significantly associated with reduced PTG.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Research into the biological predictors of posttrauma responses, particularly PTG and resilience, is limited and still developing.

    “In contrast, research into the biological predictors of posttrauma responses, particularly PTG and resilience, is limited and still developing (Mehta, Miller, Bruenig, David & Shakespeare-Finch, 2020;Schubert, Schmidt & Rosner, 2016).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Mehta et al., 2020 source
    • cites Schubert et al., 2016 source

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

    Interpretationreasoning

    The association of methylation of NR3C1 and FKBP5 only with low PTG may be due to low power of a small sample size.

    “This may be due to low power of a small sample size.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Well-being after trauma (e.g., PTG and resilience) is related to healthy HPA-axis functioning.

    “and by the same reasoning, it can be predicted that well-being after trauma (e.g., PTG and resilience) is related to healthy HPA-axis functioning.”
    Quote in the paperSubstantial claim

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

    Interpretationcitation

    This pilot study has made an important contribution to the literature by examining positive posttrauma responses rather than focusing only on potential disorder.

    “This pilot study has made an important contribution to the literature by examining positive posttrauma responses rather than focusing only on potential disorder as is common in trauma and epigenetic research.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The BRS demonstrated good internal consistency in the current sample (α = .86).

    “The current sample demonstrated good internal consistency (α =.86).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Mehta and colleagues' (2020) systematic review identified 51 studies, of which none examined PTG, and only two measured resilience.

    “For example, Mehta and colleagues (2020) systematic review of DNA methylation and gene expression patterns associated with positive and negative posttrauma responses identified 51 studies, of which none examined PTG, and only two measured resilience (Azadmarzabadi et al., 2018;Kohrt et al., 2016).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Mehta et al., 2020 source
    • cites Azadmarzabadi et al., 2018 source
    • cites Kohrt et al., 2016 source

  • May combine two claims.

    Premisecitation

    NR3C1 and FKBP5 play integral roles in activating and terminating the stress response after trauma exposure by regulating glucocorticoids and activating the negative feedback loop via the GR.

    “Therefore, NR3C1 and FKBP5 play integral roles in activating and terminating the stress response after trauma exposure by regulating glucocorticoids and activating the negative feedback loop via the GR (Binder, 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Binder, 2009 source

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

    Study design and conductnone given

    Assumptions of the data were inspected, and no breaches were detected.

    “Assumptions of the data were inspected, and no breaches were detected.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The PTGI-X demonstrated strong reliability in the current sample (α = .96).

    “The current sample verified strong reliability (α =.96).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Appropriate HPA-axis activity after trauma is associated with reduced PTSD symptom severity and heightened resilience after trauma.

    “That is, appropriate HPAaxis activity after trauma is associated with reduced PTSD symptom severity and heightened resilience after trauma.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Bonferroni multiple testing correction was performed to account for the number of CpGs tested across each gene.

    “Bonferroni multiple testing correction was performed to account for the number of CpGs tested across each gene.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Data from two participants was excluded due to poor saliva quality, resulting in a final sample of 47 participants.

    “Data from two participants was excluded due to poor saliva quality meaning the final sample was comprised of data from 47 participants.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The PCL-5 demonstrated good overall internal consistency in the current sample (α = .94).

    “The current sample corroborated good overall internal consistency (α = .94).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Methylation of NR3C1 may result in heightened gene expression, reduced PTG after trauma and dysfunctional HPA-axis function.

    “Therefore, methylation of NR3C1 may result in heightened gene expression, reduced PTG after trauma and dysfunctional HPA-axis function.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bakusic et al., 2017 source
    • cites Dudley et al., 2011 source
    • cites Watkeys et al., 2018 source

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

    Premisecitation

    The PTGI-X has shown high internal consistency in US (α = .97), Turkish (α = .96) and Japanese samples (α = .95).

    “The PTGI-X has shown high internal consistency in US (α = .97),Turkish (α = .96)and Japanese samples (α = .95;Tedeschi et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tedeschi et al., 2017 source

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

    Premisecitation

    Individuals who are resilient after trauma may still experience distress, however this distress does not disrupt their ability to function in a healthy way.

    “Individuals who are resilient after trauma may still experience distress, however this distress does not disrupt their ability to function in a healthy way (Bonanno & Diminich, 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bonanno & Diminich, 2013

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Study design and conductnone given

    The study is limited by its cross-sectional candidate gene design.

    “The study is also limited by its cross-sectional candidate gene design.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    These two different methylation patterns tend to increase gene expression, and have previously been associated with heightened distress and PTSD symptoms.

    “These two different methylation patterns tend to increase gene expression (Bakusic et al., 2017;Dudley et al., 2011), and have previously been associated with heightened distress and PTSD symptoms (see Watkeys et al., 2018 review).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bakusic et al., 2017 source
    • cites Dudley et al., 2011 source
    • cites Watkeys et al., 2018 source

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

    Premisecitation

    The BRS has previously shown high convergent and divergent validity, high discriminant predictive validity and strong reliability, and good reliability within an Australian paramedic population (α = .88).

    “The scale has previously shown high convergent and divergent validity, high discriminant predictive validity and strong reliability (Smith et al., 2008), and good reliability within an Australian paramedic population (α = .88;Shakespeare-Finch & Daley, 2017).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Smith et al., 2008 source
    • cites Shakespeare-Finch & Daley, 2017

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation

    The functional outcome of UTR methylation remains uncertain.

    “However, the functional outcome of UTR methylation remains uncertain (Aran et al., 2011;Martino & Saffrey, 2015).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Aran et al., 2011 source
    • cites Martino & Saffrey, 2015 source

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

    Premisecitation

    Methylation and expression of NR3C1 promotor associated regions has been consistently implicated in the pathophysiology of PTSD and other related disorders such as depression.

    “This replicates previous findings where methylation and expression of NR3C1 promotor associated regions has been consistently implicated in the pathophysiology of PTSD and other related disorders such as depression (see Bakusic et al., 2017;Watkeys et al., 2018 reviews)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bakusic et al., 2017 source
    • cites Watkeys et al., 2018 source

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

    Premisecitation

    The PCL-5 has demonstrated internal consistency, test-retest reliability, convergent validity and discriminant validity in US trauma-exposed students.

    “The PCL-5 has demonstrated internal consistency, test-retest reliability, convergent validity and discriminant validity in US trauma-exposed students (Blevins, Weathers, Davis, Witte & Domino, 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Blevins et al., 2015 source
29 of 29

  • The paper relies on this without support.

    Salivary DNA methylation of NR3C1 and FKBP5 reflects HPA-axis function relevant to posttrauma responses.

    “and suggests that methylation of this region may be linked to poor HPA-axis function.”

  • The paper relies on this without support.

    The cross-sectional associations between methylation and posttrauma responses reflect a directional influence of methylation on responses rather than reverse causation.

    “Methylation in FKBP5 site cg07485685 was a predictor of both PTSD symptom severity and resilience in opposite directions.”
2 of 2

Self-check

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

Each contradiction between two passages listed here was confirmed by an independent check.

  • The discussed PTSD-associated NR3C1 site differs from the reported site

    Major

    The discussion names cg03906910 as a significant promoter-associated NR3C1 site for PTSD symptom severity. Table 3, which says it reports the significant sites, instead lists cg19645279 in the gene body as the NR3C1 PTSD site.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. [11]11. Bonanno, G. A., & Diminich, E. D. (2013). Positive adjustment to adversity: Trajectories of minimal-impact resilience and emergent resilience. The Journal of Child Psychology and Pscyhiatry, 54, 378-401. doi: 10.1111/jcp.12021 · DOI

Cited by

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Related

Authors
Miller, O., Shakespeare-Finch, J., Bruenig, D., & Mehta, D.
Affiliations
Queensland University of Technology (AU)
ORCID
Venue
Psychological Trauma: Theory, Research, Practice, and Policy
Publisher
American Psychological Association (APA)
Published
2020-10
Volume
12
Issue
7
Pages
750-755
ISSN
  • 1942-9681 (ISSN-L)
  • 1942-969X
DOI
10.1037/tra0000574
OpenAlex
W3013613463
Cited by
56
References
38
Citations by year
2026: 7 · 2025: 12 · 2024: 7 · 2023: 12 · 2022: 9 · 2021: 7 · 2020: 2
FWCI
2.99
Type
journal article
Language
en
Open access
Locations
  • Psychological Trauma Theory Research Practice and Policy (publishedVersion)
  • PubMed (publishedVersion)
  • QUT ePrints (Queensland University of Technology) (submittedVersion)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
Keywords
DNA methylation, NR3C1, FKBP5, post-traumatic stress disorder, posttraumatic growth, resilience, PTSD symptom severity, epigenetics, glucocorticoid receptor, cortisol receptor, salivary biomarkers
MeSH terms
Posttraumatic Growth, Psychological, Tacrolimus Binding Protein 5, Adolescent, Adult, Female, Humans, Male, Pilot Projects, Receptors, Glucocorticoid, Severity of Illness Index, Stress Disorders, Post-Traumatic, DNA Methylation, Tacrolimus Binding Proteins, Resilience, Psychological, Young Adult

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