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.