Anxiety Associated Increased CpG Methylation in the Promoter of Asb1: A Translational Approach Evidenced by Epidemiological and Clinical Studies and a Murine Model

• Type of Material: Article
• Authors: Rebecca T Emeny, Helmholtz Zentrum Munchen; Jens Baumert, Helmholtz Zentrum Munchen; Anthony S Zannas, Max Planck Institute of Psychiatry; Sonja Kunze, Helmholtz Zentrum Munchen; Simone Wahl, Helmholtz Zentrum Munchen; Stella Iurato, Max Planck Institute of Psychiatry; Janine Arloth, Max Planck Institute of Psychiatry; Angelika Erhardt, Max Planck Institute of Psychiatry; Georgia Balsevich, Max Planck Institute of Psychiatry; Mathias V Schmidt, Max Planck Institute of Psychiatry; Peter Weber, Max Planck Institute of Psychiatry; Anja Kretschmer, Helmholtz Zentrum Munchen; Liliane Pfeiffer, Helmholtz Zentrum Munchen; Johannes Kruse, Justus-Liebig-Universität Gießen; Konstantin Strauch, Helmholtz Zentrum Munchen; Michael Roden, Heinrich Heine University Dusseldorf; Christian Herder, Heinrich Heine University Dusseldorf; Wolfgang Koenig, University of Ulm; Christian Gieger, Helmholtz Zentrum Munchen; Melanie Waldenberger, Helmholtz Zentrum Munchen; Annette Peters, Helmholtz Zentrum Munchen; Elisabeth B. Binder, Emory University; Karl-Heinz Ladwig, Helmholtz Zentrum Munchen
• Language: English
• Date: 2018-01-01
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Author(s)
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/npp.2017.102
• Title of Journal or Parent Work: Neuropsychopharmacology
• ISSN: 0893-133X
• Volume: 43
• Issue: 2
• Start Page: 342
• End Page: 353
• Grant/Funding Information: RTE is supported by The Dartmouth Clinical and Translational Science Institute, under award number UL1TR001086 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH).; The German Diabetes Center was supported by the Ministry of Science and Research of the State of North Rhine-Westphalia (MIWF NRW) and the German Federal Ministry of Health (BMG).; Furthermore, KORA research was supported by the portfolio area "metabolic dysfunction" by the Helmholtz Association and within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ.; ASZ is currently supported by a Marie-Sklodowska Curie fellowship (H2020 grant# 653240).; The KORA study was initiated and financed by the Helmholtz Zentrum München—German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria.; The investigations of the MPIP cohort were supported by ERA–NET NEURON (AnxBio).; This study was supported in part by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD).
• Keywords: Pharmacology & Pharmacy; DNA METHYLATION; INFLAMMATION; POSTTRAUMATIC-STRESS-DISORDER; Neurosciences & Neurology; PSYCHIATRIC-DISORDERS; Science & Technology; Life Sciences & Biomedicine; CYTOKINE SIGNALING SOCS; ANKYRIN REPEAT; Psychiatry; NEGATIVE REGULATORS; GENE; PANIC DISORDER; Neurosciences; DEPRESSIVE-LIKE
• Research Categories: Health Sciences, Public Health; Health Sciences, Epidemiology

Abstract

Epigenetic regulation in anxiety is suggested, but evidence from large studies is needed. We conducted an epigenome-wide association study (EWAS) on anxiety in a population-based cohort and validated our finding in a clinical cohort as well as a murine model. In the KORA cohort, participants (n=1522, age 32-72 years) were administered the Generalized Anxiety Disorder (GAD-7) instrument, whole blood DNA methylation was measured (Illumina 450K BeadChip), and circulating levels of hs-CRP and IL-18 were assessed in the association between anxiety and methylation. DNA methylation was measured using the same instrument in a study of patients with anxiety disorders recruited at the Max Planck Institute of Psychiatry (MPIP, 131 non-medicated cases and 169 controls). To expand our mechanistic understanding, these findings were reverse translated in a mouse model of acute social defeat stress. In the KORA study, participants were classified according to mild, moderate, or severe levels of anxiety (29.4%/6.0%/1.5%, respectively). Severe anxiety was associated with 48.5% increased methylation at a single CpG site (cg12701571) located in the promoter of the gene encoding Asb1 (β-coefficient=0.56 standard error (SE)=0.10, p (Bonferroni)=0.005), a protein hypothetically involved in regulation of cytokine signaling. An interaction between IL-18 and severe anxiety with methylation of this CpG cite showed a tendency towards significance in the total population (p=0.083) and a significant interaction among women (p=0.014). Methylation of the same CpG was positively associated with Panic and Agoraphobia scale (PAS) scores (β=0.005, SE=0.002, p=0.021, n=131) among cases in the MPIP study. In a murine model of acute social defeat stress, Asb1 gene expression was significantly upregulated in a tissue-specific manner (p=0.006), which correlated with upregulation of the neuroimmunomodulating cytokine interleukin 1 beta. Our findings suggest epigenetic regulation of the stress-responsive Asb1 gene in anxiety-related phenotypes. Further studies are necessary to elucidate the causal direction of this association and the potential role of Asb1-mediated immune dysregulation in anxiety disorders.