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

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

DOI: https://doi.org/10.1038/s41398-018-0278-4
URL: https://www.nature.com/articles/s41398-018-0278-4
Additional URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC61955...
Document Type: Article
Year of publication: 2018
The title of a journal, publication series: Translational Psychiatry
Volume: 8
Issue number: Article 226
Page range: 1-12
Place of publication: London
Publishing house: Nature Publ. Group
ISSN: 2158-3188
Publication language: English
Institution: School of Social Sciences > Klinische u. Biologische Psychologie u. Psychotherapie (Alpers 2010-)
Subject: 150 Psychology
Abstract: Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAsregulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulatingnoradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fearand anxiety. In silico prediction of microRNA regulation ofSLC6A2was confirmed by luciferase reporter assays andidentified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases=0.431, MAFcontrols=0.368) upstream ofMIR579was 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 effectiveMIR579expression andSLC6A2repression in vivo (p=0.041). Healthy individuals carrying at least one (T)-allele showed a brainactivation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrainand limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showedelevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270)=5.47,p=0.005). Fine-tuning ofnoradrenaline homeostasis by aMIR579genetic variation modulated central and peripheral sympathetic noradrenergicactivation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in theetiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.

Dieser Eintrag ist Teil der Universitätsbibliographie.

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