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Emeny, R.T. ; Baumert, J.J. ; Zannas, A.S.* ; Kunze, S. ; Wahl, S. ; Iurato, S.* ; Knauer-Arloth, J. ; Erhardt, A.* ; Balsevich, G.* ; Schmidt, M.V.* ; Weber, P.* ; Kretschmer, A. ; Pfeiffer, L. ; Kruse, J.* ; Strauch, K. ; Roden, M.* ; Herder, C.* ; Koenig, W.* ; Gieger, C. ; Waldenberger, M. ; Peters, A. ; Binder, E.B.* ; Ladwig, K.-H.

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, 342-353 (2018)

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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.

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