Oxytocin receptor gene methylation: converging multilevel evidence for a role in social anxiety
Open accessAbstract
Social anxiety disorder (SAD) is a commonly occurring and highly disabling disorder. The neuropeptide oxytocin and its receptor (OXTR) have been implicated in social cognition and behavior. This study-for the first time applying a multilevel epigenetic approach-investigates the role of OXTR gene methylation in categorical, dimensional, and intermediate neuroendocrinological/neural network phenotypes of social anxiety. A total of 110 unmedicated patients with SAD and matched 110 controls were analyzed for OXTR methylation by direct sequencing of sodium bisulfite-converted DNA extracted from whole blood. Furthermore, OXTR methylation was investigated regarding SAD-related traits (Social Phobia Scale (SPS) and Social Interaction Anxiety Scale (SIAS)), salivary cortisol response during the Trier social stress test (TSST), and amygdala responsiveness to social phobia related verbal stimuli using fMRI. Significantly decreased OXTR methylation particularly at CpG Chr3: 8 809 437 was associated with (1) the categorical phenotype of SAD (p<0.001, Cohen's d=0.535), (2) increased SPS and SIAS scores (p<0.001), (3) increased cortisol response to the TSST (p=0.02), and (4) increased amygdala responsiveness during social phobia-related word processing (right: p(corr)<0.001; left: p(corr)=0.005). Assuming that decreased OXTR methylation confers increased OXTR expression, the present finding may reflect a compensatory upregulation for pathologically reduced oxytocin levels or a causally relevant increased OXTR activation in SAD and related traits. OXTR methylation patterns might thus serve as peripheral surrogates of oxytocin tone and aid in establishing accessible biomarkers of SAD risk allowing for indicated preventive interventions and personalized treatment approaches targeting the oxytocin system.
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In social phobia, OXTR methylation was related to differential amygdala reactivity to social phobia-related verbal stimuli.
“In social phobia, OXTR methylation was related to differential amygdala reactivity to social phobia-related verbal stimuli (Ziegler et al., 2015).”
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 Ziegler et al., 2015
Based on effect sizes from studies of other oxytocin genes, particularly OXTR, a sample of at least 66 participants was estimated to be adequate for testing each hypothesis.
“based on effect sizes reported in studies investigating other oxytocin genes (19,20,46,47), namely OXTR, and behavior or brain associations, we estimated that a sample size of 66 or larger would be adequate to test each of our hypotheses.”
From Epigenetic modification of <i>OXT</i> and human sociability (2016) · cites this paper as [20]
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- Authors
- Ziegler, C., Dannlowski, U., Bräuer, D., Stevens, S., Laeger, I., Wittmann, H., Kugel, H., Dobel, C., Hurlemann, R., Reif, A., Lesch, K.-P., Heindel, W., Kirschbaum, C., Arolt, V., Gerlach, A. L., Hoyer, J., Deckert, J., Zwanzger, P., & Domschke, K.
- Affiliations
- University of Würzburg (DE)
- University of Münster (DE)
- Technische Universität Dresden (DE)
- University of Cologne (DE)
- University of Bonn (DE)
- Corresponding author
- Domschke, Katharina
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2015-01-07
- Volume
- 40
- Issue
- 6
- Pages
- 1528-1538
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC4397412
- OpenAlex
- W2104323563
- Cited by
- 193
- References
- 76
- Citations by year
- 2026: 12 · 2025: 10 · 2024: 18 · 2023: 12 · 2022: 11 · 2021: 16 · 2020: 24 · 2019: 15 · 2018: 19 · 2017: 23 · 2016: 16 · 2015: 17
- FWCI
- 41.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- Deutsche Forschungsgemeinschaft (TRR‐58, 602805, FOR 2107, SFB TRR 58)
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- oxytocin receptor, social anxiety disorder, epigenetics, oxytocin, salivary cortisol, Trier Social Stress Test, biomarkers, oxytocinergic system
- MeSH terms
- Adult, Amygdala, Anxiety Disorders, Female, Humans, Hydrocortisone, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Psychiatric Status Rating Scales, Saliva, Social Behavior, Genetic Variation, Receptors, Oxytocin, 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 ›
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