A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
ID 4487911
Author(s) Hommers, L. G.; Richter, J.; Yang, Y.; Raab, A.; Baumann, C.; Lang, K.; Schiele, M. A.; Weber, H.; Wittmann, A.; Wolf, C.; Alpers, G. W.; Arolt, V.; Domschke, K.; Fehm, L.; Fydrich, T.; Gerlach, A.; Gloster, A. T.; Hamm, A. O.; Helbig-Lang, S.; Kircher, T.; Lang, T.; Pane-Farre, C. A.; Pauli, P.; Pfleiderer, B.; Reif, A.; Romanos, M.; Straube, B.; Stroehle, A.; Wittchen, H. -U.; Frantz, S.; Ertl, G.; Lohse, M. J.; Lueken, U.; Deckert, J.
Author(s) at UniBasel Gloster, Andrew
Year 2018
Title A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety
Journal Translational Psychiatry
Volume 8
Pages / Article-Number 1-12
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 (MAF(cases) = 0.431, MAF(controls) = 0.368) upstream of MIR579 was associated with panic disorder in patients (p(allelic) = 0.004, n(cases) = 506, n(controls) = 506) and with higher trait anxiety in healthy individuals (p(ASI) = 0.029, p(ACQ) = 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.
Publisher Nature Publishing Group
ISSN/ISBN 2158-3188
edoc-URL https://edoc.unibas.ch/69320/
Full Text on edoc No
Digital Object Identifier DOI 10.1038/s41398-018-0278-4
ISI-Number 000447952900002
Document type (ISI) Article

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