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

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Zannas,  Anthony S.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;
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Iurato,  Stella
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Arloth,  Janine
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;
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Erhardt,  Angelika
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Balsevich,  Georgia
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

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Schmidt,  Mathias V.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

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Weber,  Peter
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Binder,  Elisabeth B.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;
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Citation

Emeny, R. T., Baumert, J., Zannas, A. S., Kunze, S., Wahl, S., Iurato, S., et al. (2018). Anxiety Associated Increased CpG Methylation in the Promoter of Asb1: A Translational Approach Evidenced by Epidemiological and Clinical Studies and a Murine Model. NEUROPSYCHOPHARMACOLOGY, 43(2), 342-353. doi:10.1038/npp.2017.102.


Cite as: http://hdl.handle.net/21.11116/0000-0002-6F51-7
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 (beta-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 (beta = 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.