Abstract
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: pcorr<0.001; left: pcorr=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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Acknowledgements
The present project was supported by the Deutsche Forschungsgemeinschaft (DFG), SFB-TRR-58, projects C02 (to KD, KPL, and JD), Z02 (to JD and AR) and A05 (to KPL), and FOR 2107, project WP1 (to UD), a grant by the Interdisziplinäres Zentrum für Klinische Forschung (IZKF), University of Muenster (Do3/021/10 to CD and PZ), and the European Community (AGGRESSOTYPE FP7/No. 602805 to AR and KPL). The contributions of JH and CK were supported by the Deutsche Forschungsgemeinschaft (DFG), grants HO 1900/6-1 to JH and KI 537/26-1 to CK. AR was supported by the Interdisziplinäres Zentrum für Klinische Forschung (IZKF), University of Wuerzburg (N-221). We gratefully acknowledge the skilful technical and intellectual support by Dr Nicola Tidow, Carola Gagel, and Kathrin Schwarte.
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Ziegler, C., Dannlowski, U., Bräuer, D. et al. Oxytocin Receptor Gene Methylation: Converging Multilevel Evidence for a Role in Social Anxiety. Neuropsychopharmacol 40, 1528–1538 (2015). https://doi.org/10.1038/npp.2015.2
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