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

  • 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.

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Author:Leif Hommers, Jan Richter, Yunbo Yang, Annette Raab, Christian Baumann, Katharina Lang, Miriam A. Schiele, Heike Weber, André Wittmann, Christiane Wolf, Georg W. Alpers, Volker Arolt, Katharina Domschke, Lydia Fehm, Thomas Fydrich, Alexander Gerlach, Andrew T. Gloster, Alfons Hamm, Sylvia Helbig-Lang, Tilo Kircher, Thomas Lang, Christiane A. Pané-Farré, Paul Pauli, Bettina Pfleiderer, Andreas ReifORCiDGND, Marcel Romanos, Benjamin Straube, Andreas Ströhle, Hans-Ulrich Wittchen, Stefan Frantz, Georg Ertl, Martin Lohse, Ulrike Lüken, Jürgen Deckert
URN:urn:nbn:de:hebis:30:3-500276
DOI:https://doi.org/10.1038/s41398-018-0278-4
ISSN:2158-3188
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/30341278
Parent Title (English):Translational Psychiatry
Publisher:Nature Publishing Group
Place of publication:London
Document Type:Article
Language:English
Year of Completion:2018
Date of first Publication:2018/10/19
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/04/23
Tag:Clinical genetics; Psychiatric disorders
Volume:8
Issue:1, Art. 226
Page Number:12
First Page:1
Last Page:12
Note:
Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
HeBIS-PPN:450551504
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0