Universität zu Köln

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. and Deckert, J. (2018). A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety. Transl. Psychiatr., 8. LONDON: NATURE PUBLISHING GROUP. ISSN 2158-3188

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hommers, L. G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Richter, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Yang, Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Raab, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Baumann, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lang, K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schiele, M. A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber, H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wittmann, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wolf, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Alpers, G. W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Arolt, V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Domschke, K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fehm, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fydrich, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gerlach, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gloster, A. T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hamm, A. O. UNSPECIFIED UNSPECIFIED UNSPECIFIED Helbig-Lang, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kircher, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lang, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pane-Farre, C. A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pauli, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pfleiderer, B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Reif, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Romanos, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Straube, B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stroehle, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wittchen, H. -U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Frantz, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ertl, G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lohse, M. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lueken, U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Deckert, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-169149
DOI:	10.1038/s41398-018-0278-4
Journal or Publication Title:	Transl. Psychiatr.
Volume:	8
Date:	2018
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2158-3188
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NOREPINEPHRINE TRANSPORTER GENE; BEHAVIORAL NEUROSCIENCE PERSPECTIVE; PANIC DISORDER; AGORAPHOBIC COGNITIONS; CANDIDATE GENE; MICRORNA; ETIOLOGY; DYSREGULATION; ASSOCIATION; ACTIVATION Multiple languages Psychiatry Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16914