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Cited by 91Neuroendocrine regulation and behaviorNeurotransmitter Receptor Influence on BehaviorEpigenetics and DNA Methylation

Epigenetic modification of OXT and human sociability

Open access
Haas, Brian W., Filkowski, Megan M., Cochran, R. Nick, Denison, Lydia, Ishak, Alexandra, Nishitani, Shota, Smith, Alicia K.·2016·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1602809113PMC PMC4941462
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Abstract

Significance: Elucidating the genetic and biological substrates of social behavior serves to advance the way basic human nature is understood and improves the way genetic and biological markers can be used to prevent, diagnose, and treat people with impairments in social cognition and behavior. This study shows that epigenetic modification of the structural gene for oxytocin ( OXT ) is an important factor associated with individual differences in social processing, including self-report, behavior, and brain function and structure in humans.

AI snapshot

Written from the paper’s full text.

TL;DR

In 129 adults, greater OXT promoter DNA methylation was associated with less secure attachment, poorer emotion recognition, reduced social-cognitive brain activity, and smaller right fusiform gray matter volume. These cross-modal associations suggest epigenetic modification of OXT relates to individual differences in human sociability.

Key findings

  • Greater OXT DNA methylation was associated with higher anxious attachment style [R² = 0.06, t(1,128) = 2.83, P = 0.005, r = 0.24], but not avoidant attachment style [r = 0.03, t(1,128) = 0.38, P = 0.71]; the anxious-attachment association remained significant with sex and age as covariates (P = 0.006).
  • Greater OXT DNA methylation was associated with lower overall emotion-recognition accuracy [r = −0.21, t(1,127) = 2.41, P = 0.017], and specifically for angry (r = −0.21, P = 0.019) and sad (r = −0.20, P = 0.027) expressions, but not happy (P = 0.91) or fearful (P = 0.95) expressions; reaction time was not significant (P = 0.36).
  • During fMRI, greater OXT DNA methylation was associated with reduced right STS activity during emotional perspective-taking [k = 407; MNI: 48, −38, 4; t = 4.59, P < 0.001] and during emotion attribution with reduced right STS [k = 60; MNI: 42, −60, 2; t = 3.03, P = 0.002], right fusiform/middle occipital gyrus [k = 106; MNI: 40, −60, −10; t = 3.26, P = 0.001], right inferior frontal gyrus [k = 92; MNI: 58, 26, 24; t = 3.23, P = 0.001], and left fusiform activity [k = 101; MNI: −26, −72, −8; t = 3.04, P = 0.001]; no positive activity clusters were found.
  • Greater OXT DNA methylation was associated with reduced right fusiform gyrus gray matter volume [k = 354; MNI: 48, −57, −14; t = 4.44, P < 0.0005]; no positive gray matter associations were found, and methylation was not associated with total brain (P = 0.23), gray matter (P = 0.42), or white matter (P = 0.45) volume.

Methods

  • Cross-modal study testing associations between OXT promoter DNA methylation and sociability measures: self-reported attachment style (ASQ), dynamic facial emotion recognition, two social-cognitive fMRI tasks (emotional perspective-taking and emotion attribution), and structural MRI voxel-based morphometry.
  • Participants were 129 fluent English-speaking adults (72 females, 57 males; mean age = 21.37 y, SD = 3.49 y) from the University of Georgia and surrounding community; genetic testing n = 129, ASQ n = 129, emotion recognition n = 128, emotional perspective-taking fMRI n = 121, emotion attribution fMRI n = 120, structural neuroimaging n = 121.
  • DNA was extracted from saliva, bisulfite-treated, and analyzed with EpiTYPER to quantify methylation across nine CpG sites in the OXT promoter (chr20:3,052,266–3,053,162; hg19); average methylation was used. Analyses included regression with methylation as predictor, confirmatory models with sex and age covariates, whole-brain fMRI regression, and VBM with total brain volume, sex, and age as covariates.

Limitations

  • The paper states the sample size was modest (n ranged from 120–129), that this is the first empirical study on OXT methylation in humans, and that the effect-size estimate does not account for factors such as publication bias, so results should be interpreted with caution until replicated in an independent cohort.
  • The paper also states that other oxytocin signaling genes such as CD38 were not considered; there may not be a linear relationship between DNA methylation in this region and oxytocin protein levels; the sample was relatively homogeneous with a narrow age range (18–35 y); and the findings provide no direct empirical information about oxytocin production, function, or accessibility in the central nervous system.
  • Additional limitations evident from the text: OXT expression was not measured directly; saliva methylation may not reflect methylation in relevant brain regions; the majority of CpG sites were correlated and average methylation was analyzed, so a subset of sites may be just as informative; and the cross-sectional correlational design cannot establish causality.

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

Integrity signals

Registry

Crossref · 10.1073/pnas.1602809113

Cites

62 of 62 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 15 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    During emotion attribution, greater OXT methylation was linked to lower activity in right STS, right Fus/MOG, right IFG, and left Fus.

    “greater OXT DNA methylation values were associated with reduced right STS (k = 60; MNI: 42, -60, 2; t = 3.03, P = 0.002), right fusiform gyrus/middle occipital gyrus (Fus/MOG) (k = 106; MNI: 40, -60, -10; t = 3.26, P = 0.001), right inferior frontal gyrus (IFG) (k = 92; MNI: 58, 26, 24; t = 3.23, P = 0.001) and left fusiform (Fus) activity (k = 101; MNI: -26, -72, -8; t = 3.04, P = 0.001)”
    Quote in the paperSubstantial claim
  • Findingown data

    Higher anxious attachment scores were linked to greater methylation of OXT.

    “Greater OXT DNA methylation was associated with higher anxious attachment-style scores (r = 0.24).”
    Quote in the paperSubstantial claim
  • Findingown data

    Greater OXT methylation was linked to smaller right fusiform gyrus gray matter volume.

    “greater OXT DNA methylation values were associated with reduced gray matter volume within the right fusiform gyrus (Fus)”
    Quote in the paperSubstantial claim
  • Findingown data

    Avoidant attachment style showed no significant relationship with OXT methylation.

    “OXT methylation and avoidant attachment style were not significantly associated [r = 0.03, t(1, 128) = 0.38, P = 0.71].”
    Quote in the paperNot a substantial claim
  • Findingown data

    During emotional perspective-taking, greater OXT methylation was linked to lower right STS activity.

    “greater OXT DNA methylation values were associated with reduced right superior temporal sulcus (STS) activity during emotional perspective-taking”
    Quote in the paperSubstantial claim
  • May combine two claims. 10
  • Classified as probably not a substantial claim. 13
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    For angry and sad faces, greater OXT methylation predicted lower recognition accuracy, while happy and fearful faces showed no such link.

    “greater OXT DNA methylation was associated with lower emotion recognition accuracy for angry (r = -0.21,P = 0.019) and sad (r = -0.20,P = 0.027) facial expressions, but not for happy (P = 0.91) or fearful (P = 0.95) facial expressions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    OXT DNA methylation was associated with ASQ scores and emotion-recognition accuracy.

    “Scatterplot displaying the association between OXT DNA methylation and ASQ (A) and emotion-recognition accuracy (B).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given
    § Epigenetic modification of OXT and human sociability

    Oxytocin is a neuropeptide linked to social behaviors in humans and other mammals.

    “Oxytocin is a neurohypophysial peptide synthesized in the hypothalamus in the brain, linked to a wide range of social behaviors in humans and other mammals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The STS result aligns with oxytocin increasing STS activity in autism and with OXTR methylation relating to STS activity.

    “The current finding is consistent with a prior neuroimaging study demonstrating that oxytocin administration enhances STS activity in individuals with autism (37), and with a recent finding that OXTR methylation is associated with STS activity (6).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [37] source

      Not checked in the free run.

    • cites [6] source

      Not checked in the free run.

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

    Premisecitation

    The STS is a key mentalizing region and is altered in social-cognitive conditions such as autism.

    “The STS is an important brain region within the mentalizing network (24) and is functionally and structurally aberrant in conditions characterized by deficits in social-cognition, such as autism (35).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] source

      Not checked in the free run.

    • cites [35] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The finding suggests OXT may shape social bonding during development and intimate relationship formation.

    “The current finding indicates that OXT may influence social bonding during development and affects the way people form and maintain intimate social relationships with others.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Lower OXT DNA methylation corresponds to higher OXT expression in humans.

  • May combine two claims.

    Premisecitation

    In bovine cells, OXT expression is accompanied by low promoter methylation, and lack of expression by high methylation.

    “Bovine cells that express OXT have low levels of promoter methylation, whereas cells that do not express OXT have high methylation levels in this region (28).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The study did not directly measure OXT expression.

    “within this study we did not measure OXT expression directly”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The results provide cross-modal evidence that OXT relates to human sociability and that its epigenetic modification contributes to sociability differences.

    “Combined, these findings provide empirical, cross-modal evidence that OXT is a gene linked to human sociability and that epigenetic modification of OXT confers individual differences in human sociability.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Lower OXT DNA methylation corresponds to higher OXT expression in humans.
    • Rests on an assumption: The observed associations are not due to unmeasured confounding or reverse causation.

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

    Study design and conductnone given

    The findings do not provide direct empirical information about the production, function, or accessibility of oxytocin in the central nervous system.

    “Finally, our findings do not provide any direct empirical information regarding the production, function, or accessibility of oxytocin within the central nervous system.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    A significance threshold of P = 0.025 was adopted to protect against type 1 errors.

    “We adopted a significance threshold of P = 0.025 to protect against type 1 errors.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Confirmatory multiple regression analyses were performed with sex and age entered as covariates.

    “Confirmatory multiple regression analyses were performed while sex and age were entered as covariates using the same statistical procedures.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The VBM analysis included age, sex, and total brain volume as covariates.

    “For all analyses, age, sex, and total brain volume were entered as covariates.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    In whole-brain analysis, reporting was limited to clusters that passed both the nonparametric and parametric procedures.

    “For whole-brain analysis, only clusters that survived following both the nonparametric and parametric statistical procedures are reported (61).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    The sample was relatively homogeneous and consisted of individuals within a narrow age range of 18 to 35 years.

    “Fourth, our sample was relatively homogeneous, and was comprised of people within a relatively narrow age range (18-35 y).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Genetic testing was completed by 129 participants, the ASQ by 129, the emotion recognition task by 128, the emotional perspective-taking fMRI task by 121, the emotion attribution fMRI task by 120, and structural neuroimaging by 121.

    “From this total sample, 129 completed genetic testing, 129 completed the Attachment Style Questionnaire (ASQ), 128 completed the emotion recognition task, 121 completed the emotional perspective-taking fMRI task, 120 completed the emotion attribution fMRI task, and 121 completed structural neuroimaging.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    In this sample, internal consistency for the anxious and avoidant attachment scales was 0.72 and 0.80, respectively.

    “For the current sample, reliability analysis for anxious and avoidant attachment scales yielded Cronbach's α values of 0.72 and 0.80, respectively.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Every participant underwent screening for neurological and psychiatric conditions through self-report and for MRI contraindications.

    “All participants were screened for neurological and psychiatric conditions (via self-report) and MRI contraindications.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The study's sample size was modest, ranging from 120 to 129 participants.

    “First and foremost, the sample size for this study was modest (n ranged from 120-129).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    A combined nonparametric and parametric statistical approach was used to protect against false-positive (type 1) errors.

    “To protect against false-positive (type 1) errors, we used a combined nonparametric and parametric statistical approach.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Interpretationreasoning

    Methylation of different oxytocin pathway genes may affect STS function in opposite directions.

    “These findings indicate that methylation of specific genes within the oxytocin signaling pathway affects the function of the STS differently.”
    Quote in the paperSubstantial claim
21 of 21

  • The authors state this as an assumption.

    Lower OXT DNA methylation corresponds to higher OXT expression in humans.

    “presumably yielding higher OXT expression”

  • The paper relies on this without support.

    The observed associations are not due to unmeasured confounding or reverse causation.

    “epigenetic modification of OXT confers individual differences in human sociability”

  • The paper relies on this without support.

    This is the first empirical study on OXT methylation in humans.

    “To our knowledge, this is the first empirical study on OXT methylation in humans.”
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?

  • Lower DNA methylation levels of the gene coding for the oxytocin prepropeptide (OXT) have been linked to more secure attachment styles along with a superior ability to correctly recognize emotional facial expressions and thus potentially mediate higher resilience against mental disorders characterized by various forms of decreased social functioning.

    “lower DNA methylation levels of the gene coding for the oxytocin prepropeptide (OXT) have been linked to more secure attachment styles along with a superior ability to correctly recognize emotional facial expressions and thus potentially mediate higher resilience against mental disorders characterized by various forms of decreased social functioning (Haas et al., 2016).”

    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 Haas et al., 2016

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Epigenetic changes in genes that regulate oxytocin pathways, along with endogenous oxytocin levels, are related to how people form and maintain close social relationships.

    “Our findings are in line with emerging evidence (Dadds et al., 2014; Haas et al., 2016) suggesting that epigenetic modification of genes regulating OT pathways and endogenous OT levels are associated with the way people form and maintain intimate social relationships with others.”

    From Associations between oxytocin receptor gene (OXTR) methylation, plasma oxytocin, and attachment across adulthood (2019) · cites this paper as Haas et al., 2016

  • Haas et al. found no significant effects for attachment avoidance.

    “In fact, Haas et al. found no significant effects for attachment avoidance.”

    From Associations between oxytocin receptor gene (OXTR) methylation, plasma oxytocin, and attachment across adulthood (2019) · cites this paper as Haas et al., 2016

  • People with lower DNA methylation of the OXT gene tend to have more secure attachment, marked by less attachment anxiety.

    “Our findings regarding attachment anxiety are in line with a recent study showing that individuals with lower DNA methylation levels of the structural gene for oxytocin (OXT) have more secure attachment characterized by lower levels of attachment anxiety (Haas et al., 2016).”

    From Associations between oxytocin receptor gene (OXTR) methylation, plasma oxytocin, and attachment across adulthood (2019) · cites this paper as Haas et al., 2016

  • Epigenetic modifications of the OT gene predict many aspects of human sociability.

    “Consistent with these observations, a recent study identified epigenetic modifications of the OT gene that predicts many aspects of human sociability”

    From Oxytocin and Social Relationships: From Attachment to Bond Disruption (2017) · cites this paper as Haas et al. 2016

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Related

Authors
Haas, B. W., Filkowski, M. M., Cochran, R. N., Denison, L., Ishak, A., Nishitani, S., & Smith, A. K.
Affiliations
  • University of Georgia (US)
  • Emory University (US)
  • Stanford Medicine (US)
Corresponding author
Haas, Brian W.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2016-06-20
Volume
113
Issue
27
Pages
E3816-23
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1602809113
PMC
PMC4941462
OpenAlex
W2468956824
Semantic Scholar
96ab44f58dc5e0bb737a4e041627b625233aa1ac
Cited by
91
References
62
Citations by year
2026: 6 · 2025: 1 · 2024: 13 · 2023: 5 · 2022: 4 · 2021: 9 · 2020: 14 · 2019: 11 · 2018: 14 · 2017: 13 · 2016: 1
FWCI
20.41
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
oxytocin, DNA methylation, epigenetic modifications, sociability, social attachment, facial emotion recognition, superior temporal sulcus, fusiform gyrus, gray matter volume, social cognition, individual differences
MeSH terms
Female, Humans, Male, Object Attachment, Oxytocin, Epigenesis, Genetic, Young Adult, Emotional Intelligence, Functional Neuroimaging, Social Skills

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