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Oxytocin Receptor Gene Methylation: Converging Multilevel Evidence for a Role in Social Anxiety

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Oxytocin Receptor Gene Methylation: Converging Multilevel Evidence for a Role in Social Anxiety Neuropsychopharmacology (2015) 40, 1528–1538 & 2015 American College of Neuropsychopharmacology. All rights reserved 0893-133X/15 www.neuropsychopharmacology.org Oxytocin Receptor Gene Methylation: Converging Multilevel Evidence for a Role in Social Anxiety 1,13 2,3,13 4,13 5 2,6 Christiane Ziegler , Udo Dannlowski , David Bra¨uer , Stephan Stevens , Inga Laeger , 2 7 8 9 1 10 Hannah Wittmann , Harald Kugel , Christian Dobel , Rene´ Hurlemann , Andreas Reif , Klaus-Peter Lesch , 7 11 2 5 4 Walter Heindel , Clemens Kirschbaum , Volker Arolt , Alexander L Gerlach ,Ju¨rgen Hoyer , 1 2,12,14 ,1,14 Ju¨rgen Deckert , Peter Zwanzger and Katharina Domschke* 1 2 Department of Psychiatry, University of Wu¨rzburg, Wu¨rzburg, Germany; Department of Psychiatry, University of Mu¨nster, Mu¨nster, Germany; 3 4 Department of Psychiatry, University of Marburg, Marburg, Germany; Institute of Clinical Psychology and Psychotherapy, Technische Universita¨t 5 6 Dresden, Dresden, Germany; Institute of Clinical Psychology and Psychotherapy, University of Cologne, Cologne, Germany; Institute of Psychology, University of Mu¨nster, Mu¨nster, Germany; 7Department of Clinical Radiology, University of Mu¨nster, Mu¨nster, Germany; 8Institute of Biogmagnetism and Biosignal Analysis, University of Munster, Munster, Germany; 9Division of Medical Psychology, Department of Psychiatry, ¨ ¨ 10 University of Bonn, Bonn, Germany; Division of Molecular Psychiatry, Department of Psychiatry, University of Wu¨rzburg, Wu¨rzburg, Germany; 11 12 Institute of Biopsychology, Technische Universita¨t Dresden, Dresden, Germany; kbo-Inn-Salzach-Klinikum, Wasserburg am Inn, Germany 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 (po0.001, Cohen’s d ¼ 0.535), (2) increased SPS and SIAS scores (po0.001), (3) increased cortisol response to the TSST (p ¼ 0.02), and (4) increased amygdala responsiveness during social phobia-related word processing (right: p 0.001; left: p ¼ 0.005). Assuming that corro corr 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. Neuropsychopharmacology (2015) 40, 1528–1538; doi:10.1038/npp.2015.2; published online 28 January 2015 INTRODUCTION and confers a high individual and socioeconomic burden (Stein and Stein, 2008). Social anxiety disorder (SAD) is characterized by marked Oxytocin (OT; OXT), a neuropeptide consisting of nine fear or anxiety about and avoidance of one or more social amino acids, is produced in the hypothalamic paraventri- situations that involve the possibility of being scrutinized, cular and supraoptic nuclei, is secreted mainly into the being negatively evaluated by others, or being embarrassed, posterior lobe of the pituitary gland, and binds to a G humiliated, or rejected (American Psychiatric Association, protein-coupled receptor (OTR; OXTR) widely expressed in 2013). SAD is a commonly occurring mental disorder the central nervous system. Oxytocin is frequently termed affecting 15 million adults, or 6.8% of the US population, the ‘prosocial neuropeptide’ as it facilitates social affiliative and approach behaviors, even in response to social threat, increases positive social interaction, and fosters pair *Correspondence: Professor K Domschke, Department of Psychiatry, bonding, trust, empathy, and attachment in humans and University of Wu¨rzburg, Fu¨chsleinstrasse 15, Wu¨rzburg D-97080, animals. Furthermore, oxytocin has been suggested as a Germany, Tel: +49 931 20177100, Fax: +49 931 20177109, E-mail: [email protected] promising anxiolytic pharmacotherapeutic agent in disorders 13Shared first authorship related to social dysfunctioning (for review see Bakermans- 14Shared last authorship Kranenburg and van Ijzendoorn, 2013; Meyer-Lindenberg Received 6 September 2014; revised 21 November 2014; accepted 29 et al, 2011). Specifically, in SAD, decreased baseline oxytocin November 2014; accepted article preview online 7 January 2015 plasma levels have been observed (Hoge et al, 2012), and OXTR methylation in social anxiety C Ziegler et al 1529 intranasal application of oxytocin as an adjunct to five be a diminished oxytocin synthesis and/or OXTR dysregu- weekly exposure therapy sessions significantly improved lation possibly linked to epigenetic mechanisms. Thus, in self-reported speech performance compared with placebo this study we for the first time applied a multilevel epi- (Guastella et al, 2009). On a brain network level, oxytocin genetic approach to elucidate the role of OXTR methylation attenuates excessive amygdala activation in response to in categorical, dimensional, and intermediate neuroendo- socially relevant or fear-conditioned emotional stimuli crinological/neural network phenotypes of social anxiety. In (Domes et al, 2007a; Kirsch et al, 2005; Labuschagne et al, detail, it was investigated whether OXTR methylation was 2010; Petrovic et al, 2008)—a brain activation pattern associated (1) with the categorical phenotype of SAD, (2) linked to social avoidance and phobia (Phan et al, 2006). with dimensional traits related to social anxiety in both The oxytocin system has furthermore been implicated in patients and healthy probands, (3) with cortisol response to social cognition and behavior on a genetic level: the G allele the TSST as a nonclinical intermediate phenotype of social of the 6930G4A (rs53576) variant in intron 3 of the anxiety in healthy probands, and (4) with brain activation oxytocin receptor gene (OXTR) located on chromosome correlates of social phobia-related word processing in 3p25.3 was found to be associated with beneficial social patients with SAD. traits such as increased empathy, optimism, and trust, whereas A allele carriers displayed lower empathy, lower optimism, and self-esteem, higher levels of state loneliness, more concerns about negative perceptions of company, and PATIENTS AND METHODS higher levels of physiological and dispositional stress Samples and Procedures reactivity (for review see Kumsta and Heinrichs, 2013). Recently, epigenetic modifications including methylation Overall sample. The overall sample comprised 111 SAD of the cytosine pyrimidine ring in CpG dinucleotides have patients of Caucasian descent recruited at the Department been suggested as flexible and temporally dynamic regula- of Psychiatry and the Institute of Psychology, University of tory mechanisms that are responsive to environmental Muenster, Germany (f ¼ 77, m ¼ 34; age ¼ 30.1 þ 9.9 stimuli and crucially shape gene expression. The OXTR gene years þ SD). The diagnosis of SAD was ascertained by contains a CpG island spanning exons 1 to 3 (Chr3:8 808 experienced psychiatrists and/or clinical psychologists on 962–8 811 280, GRCh37/hg19) (Kumsta et al, 2013), with the basis of medical records and structured clinical interviews evidence for increased OXTR methylation to confer (SCID-I) according to the criteria of DSM-IV (Wittchen, decreased OXTR expression: in hepatoblastoma cells, 1997). A total of 21 patients were comorbidly diagnosed methylation of this OXTR CpG island significantly sup- with a concurrent mild to moderate major depressive pressed OXTR mRNA expression by 70% (Kusui et al, episode (18.9%; data lacking for 7 patients), in line with 2001). Accordingly, Gregory et al (2009) observed methyla- epidemiological data reporting 19.5–35% of individuals with tion of two CpG sites within this island to result in a 20% primary SAD meeting diagnostic criteria for currently reduction in OXTR mRNA expression, and lower plasma comorbid or lifetime major depression, respectively oxytocin levels were associated with increased OXTR (Ohayon and Schatzberg, 2010; Stein et al, 1990), 5 patients methylation in peripheral blood (Dadds et al, 2014). Also, with specific phobia, and 1 patient with panic disorder and in murine cell lines, negative correlations between OXTR agoraphobia. Patients with psychotic disorders including methylation and mRNA expression were observed (Mamrut schizoaffective disorder, bipolar disorder, mental retarda- et al, 2013). So far, OXTR methylation of this CpG island has tion, or neurological/neurodegenerative disorders impairing been investigated with regard to several phenotypes
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