title: Oxytocin receptor gene methylation: converging multilevel evidence for a role in social anxiety.
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: 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.
authors.affiliation: Department of Psychiatry, University of Würzburg, Würzburg, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Ziegler
authors.affiliation: 1] Department of Psychiatry, University of Münster, Münster, Germany [2] Department of Psychiatry, University of Marburg, Marburg, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Dannlowski
authors.affiliation: Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Bräuer
authors.affiliation: Institute of Clinical Psychology and Psychotherapy, University of Cologne, Cologne, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Stevens
authors.affiliation: 1] Department of Psychiatry, University of Münster, Münster, Germany [2] Institute of Psychology, University of Münster, Münster, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Laeger
authors.affiliation: Department of Psychiatry, University of Münster, Münster, Germany.
authors.forename: Hannah
authors.initials: H
authors.lastname: Wittmann
authors.affiliation: Department of Clinical Radiology, University of Münster, Münster, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Kugel
authors.affiliation: Institute of Biogmagnetism and Biosignal Analysis, University of Münster, Münster, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Dobel
authors.affiliation: Division of Medical Psychology, Department of Psychiatry, University of Bonn, Bonn, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Hurlemann
authors.affiliation: Department of Psychiatry, University of Würzburg, Würzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reif
authors.affiliation: Division of Molecular Psychiatry, Department of Psychiatry, University of Würzburg, Würzburg, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.affiliation: Department of Clinical Radiology, University of Münster, Münster, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Heindel
authors.affiliation: Institute of Biopsychology, Technische Universität Dresden, Dresden, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Kirschbaum
authors.affiliation: Department of Psychiatry, University of Münster, Münster, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Arolt
authors.affiliation: Institute of Clinical Psychology and Psychotherapy, University of Cologne, Cologne, Germany.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Gerlach
authors.affiliation: Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hoyer
authors.affiliation: Department of Psychiatry, University of Würzburg, Würzburg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Deckert
authors.affiliation: 1] Department of Psychiatry, University of Münster, Münster, Germany [2] kbo-Inn-Salzach-Klinikum, Wasserburg am Inn, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Zwanzger
authors.affiliation: Department of Psychiatry, University of Würzburg, Würzburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Domschke
mesh_terms: D000328:Adult; D000679:Amygdala / Q000503:physiopathology; D001008:Anxiety Disorders / Q000235:genetics* / Q000503:physiopathology; D019175:DNA Methylation; D005260:Female; D014644:Genetic Variation; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D009483:Neuropsychological Tests; D011569:Psychiatric Status Rating Scales; D018045:Receptors, Oxytocin / Q000235:genetics*; D012463:Saliva / Q000378:metabolism; D012919:Social Behavior
chemical_list: C569600:OXTR protein, human; D018045:Receptors, Oxytocin; D006854:Hydrocortisone