A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety

Leif Hommers ,Heike Weber ,Alfons O Hamm ,Katharina Domschke ,Andrew T Gloster ,Martin J Lohse ,Miriam A Schiele ,Benjamin Straube ,Lydia Fehm ,Stefan Frantz ,Christiane A Pané-Farré ,Andreas Reif ,Volker Arolt ,Ulrike Lueken ,Christian Baumann ,Sylvia Helbig-Lang ,Paul Pauli ,Christiane Wolf ,André Wittmann ,Georg W Alpers ,Hans‐Ulrich Wittchen ,Bettina Pfleiderer ,Yang Yao ,Georg Ertl ,Thomas Lang ,Alexander L Gerlach ,Marcel Romanos ,Annette Raab ,Thomas Fydrich ,Tilo Kircher ,K Lang ,Jan Richter ,Andreas Ströhle ,Jürgen Deckert

doi:10.1038/s41398-018-0278-4

Abstract

Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.

Highlights

Anxiety disorders are a group of frequent mental disorders starting early in life and resulting from complex gene-by-environment interactions[1,2]
TagSNPs with a minor allele frequency (MAF) > 0.1 were determined for each of the ten candidate microRNA genes identified by means of luciferase reporter assays (Fig. 1) in a flanking region of 2000 bp upstream and 500 bp downstream[47]
Regulation of gene expression by microRNAs is an important mechanism in neuronal plasticity

Summary

Introduction

Anxiety disorders are a group of frequent mental disorders starting early in life and resulting from complex gene-by-environment interactions[1,2]. Panic disorder (PD) with agoraphobia (AG) is characterized by marked heritability as well as disproportionate generalization of fear to stimuli and contexts not necessarily predictive for actual danger[3,4,5]. Its clinical syndromes such as panic attacks or anxious apprehension reflect defensive states equivalent to those elicited by Hommers et al Translational Psychiatry (2018)8:226 actual danger as part of the defensive motivational system as defined by Research Domain Criteria (RDoC)[6]. Symptoms of noradrenergic excess in pheochromocytoma or symptoms elicited by alpha 2-adrenergic receptor antagonist challenge resemble symptoms of sympathetic noradrenergic activation during panic attacks[10,11] and reports on increased noradrenaline levels during panic attacks may explain these observations[12]

Methods

Results

Conclusion