DNA hypomethylation of the Kr\xfcppel-like factor 11 (KLF11) gene promoter: a putative biomarker of depression comorbidity in panic disorder and of non-anxious depression?

Leonie Kollert,Katharina Domschke,Andreas Menke,Christiane Thiel,Miriam A Schiele,Jürgen Deckert

doi:10.1007/s00702-020-02216-9

Leonie Kollert, Katharina Domschke + Show 4 more

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https://doi.org/10.1007/s00702-020-02216-9

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Abstract

Panic disorder (PD) is one of the most common anxiety disorders and often occurs comorbidly with major depressive disorder (MDD). Altered methylation of the monoamine oxidase A (MAOA) gene has been implicated in the etiology of both PD and MDD. The Krüppel-like factor 11 (KLF11; alias TIEG2), an activating transcription factor of the MAOA gene, has been found to be increased in MDD, but has not yet been investigated in PD. In an effort to further delineate the effects of the KLF11–MAOA pathway in anxiety and affective disorders, KLF11 promoter methylation was analyzed via pyrosequencing of sodium bisulfite-treated DNA isolated from human peripheral blood in two independent samples of PD patients with or without comorbid MDD in a case–control design (sample 1: N = 120) as well as MDD patients with and without anxious depression (sample 2: N = 170). Additionally, in sample 1, KLF11 methylation was correlated with Beck Depression Inventory (BDI-II) scores. No overall association of KLF11 promoter methylation with PD was detected. However, PD patients with comorbid MDD showed significant hypomethylation relative to both healthy controls (p = 0.010) and PD patients without comorbid MDD (p = 0.008). Furthermore, KLF11 methylation was negatively correlated with BDI-II scores in PD patients (p = 0.013). MDD patients without anxious features showed nominally decreased KLF11 methylation in comparison to MDD patients with anxious depression (p = 0.052). The present results suggest KLF11 promoter hypomethylation as a potential epigenetic marker of MDD comorbidity in PD or of non-anxious depression, respectively, possibly constituting a differential pathomechanism in anxiety and mood disorders.

Highlights

Panic disorder (PD) is one of the most common anxiety disorders, with lifetime prevalence rates of 2.1–4.7% (Baxter et al 2014) and a 12-month prevalence of 1.8% (Goodwin et al 2005)
PD is often comorbid with major depressive disorder (MDD; Gorman and Coplan 1996): Lifetime prevalence rates of comorbid MDD in PD are estimated at about 30–40% (Fava et al 2000; Lamers et al 2011; Kessler et al 2015), similar to the lifetime prevalence rates of comorbid MDD in the group of anxiety disorders as a whole (Kessler et al 2006)
In the overall case–control comparison between PD patients and healthy controls, no significant differences in average methylation or in DNA methylation at single CpG sites was discerned

Summary

Introduction

Panic disorder (PD) is one of the most common anxiety disorders, with lifetime prevalence rates of 2.1–4.7% (Baxter et al 2014) and a 12-month prevalence of 1.8% (Goodwin et al 2005). Tranylcypromine—has been suggested as a key player in the pathogenesis of anxiety and mood disorders (for review see Ziegler and Domschke 2018). MAOA hypomethylation has been observed to be predictive of response to pharmacological treatment in MDD (Domschke et al 2012) and to be modifiable by psychotherapeutic interventions in anxiety disorders (Ziegler et al 2016; Schiele and Domschke 2018; Schiele et al 2018; for review see Schiele et al 2020)

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