TY  - JOUR
A1  - Hommers, Leif
A1  - Richter, Jan
A1  - Yang, Yunbo
A1  - Raab, Annette
A1  - Baumann, Christian
A1  - Lang, Konstantin
A1  - Schiele, Miriam A.
A1  - Weber, Heike
A1  - Wittmann, André
A1  - Wolf, Christiane
A1  - Alpers, Georg W.
A1  - Arolt, Volker
A1  - Domschke, Katharina
A1  - Fehm, Lydia
A1  - Fydrich, Thomas
A1  - Gerlach, Alexander
A1  - Gloster, Andrew T.
A1  - Hamm, Alfons
A1  - Helbig-Lang, Sylvia
A1  - Kircher, Tilo
A1  - Lang, Thomas
A1  - Pané-Farré, Christiane A.
A1  - Pauli, Paul
A1  - Pfleiderer, Bettina
A1  - Reif, Andreas
A1  - Romanos, Marcel
A1  - Straube, Benjamin
A1  - Ströhle, Andreas
A1  - Wittchen, Hans-Ulrich
A1  - Frantz, Stefan
A1  - Ertl, Georg
A1  - Lohse, Martin
A1  - Lüken, Ulrike
A1  - Deckert, Jürgen
T1  - A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety
T2  - Translational Psychiatry
N2  - 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.
KW  - Clinical genetics
KW  - Psychiatric disorders
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/50027
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-500276
SN  - 2158-3188
N1  - 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/.
VL  - 8
IS  - 1, Art. 226
SP  - 1
EP  - 12
PB  - Nature Publishing Group
CY  - London
ER  -