title: MicroRNA hsa-miR-4717-5p regulates RGS2 and may be a risk factor for anxiety-related traits.
abstract: Regulator of G-protein Signaling 2 (RGS2) is a key regulator of G-protein-coupled signaling pathways involved in fear and anxiety. Data from rodent models and genetic analysis of anxiety-related traits and disorders in humans suggest down-regulation of RGS2 expression to be a risk factor for anxiety. Here we investigated, whether genetic variation in microRNAs mediating posttranscriptional down-regulation of RGS2 may be a risk factor for anxiety as well. 75 microRNAs predicted to regulate RGS2 were identified by four bioinformatic algorithms and validated experimentally by luciferase reporter gene assays. Specificity was confirmed for six microRNAs (hsa-miR-1271-5p, hsa-miR-22-3p, hsa-miR-3591-3p, hsa-miR-377-3p, hsa-miR-4717-5p, hsa-miR-96-5p) by disrupting their seed sequence at the 3' untranslated region of RGS2. Hsa-miR-4717-5p showed the most robust effect on RGS2 and regulated two other candidate genes of anxiety disorders (CNR1 and IKBKE) as well. Two SNPs (rs150925, rs161427) within and 1,000 bp upstream of the hostgene of hsa-miR-4717-5p (MIR4717) show a minor allele frequency greater than 0.05. Both were in high linkage disequilibrium (r(2) = 1, D' = 1) and both major (G) alleles showed a trend for association with panic disorder with comorbid agoraphobia in one of two patient/control samples (combined n(patients) = 497). Dimensional anxiety traits, as described by Anxiety Sensitivity Index (ASI) and Agoraphobic Cognitions Questionnaire (ACQ) were significantly higher among carriers of both major (G) alleles in a combined patient/control sample (n(combined) = 831). Taken together, data indicate that MIR4717 regulates human RGS2 and contributes to the genetic risk towards anxiety-related traits.
authors.affiliation: Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany.|Interdisciplinary Center for Clinical Research, University Hospital of Würzburg, Würzburg, Germany.|Comprehensive Heart Failure Center (CHFC), University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Leif
authors.initials: L
authors.lastname: Hommers
authors.affiliation: Interdisciplinary Center for Clinical Research, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Raab
authors.affiliation: Interdisciplinary Center for Clinical Research, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Bohl
authors.affiliation: Interdisciplinary Center for Clinical Research, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Weber
authors.affiliation: Interdisciplinary Center for Clinical Research, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Claus-Jürgen
authors.initials: CJ
authors.lastname: Scholz
authors.affiliation: Max-Planck-Institute of Psychiatry, Munich, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Erhardt
authors.affiliation: Max-Planck-Institute of Psychiatry, Munich, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Binder
authors.affiliation: Department of Psychiatry, University of Muenster, Muenster, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Arolt
authors.affiliation: Department of Clinical Psychology and Psychotherapy, University of Cologne, Cologne, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gerlach
authors.affiliation: Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany.
authors.forename: Andrew
authors.initials: A
authors.lastname: Gloster
authors.affiliation: Neuroimaging Center Mainz, Johannes Gutenberg University Medical Center, Mainz, Germany.
authors.forename: Raffael
authors.initials: R
authors.lastname: Kalisch
authors.affiliation: Department of Psychiatry and Psychotherapy, Philipps University Marburg, Marburg, Germany.
authors.forename: Tilo
authors.initials: T
authors.lastname: Kircher
authors.affiliation: Institute for Systems Neuroscience, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Lonsdorf
authors.affiliation: Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ströhle
authors.affiliation: Department of Psychiatry, University of Muenster, Muenster, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Zwanzger
authors.affiliation: Department of Biomedicine and Centre for integrative Sequencing (iSEQ), Aarhus University, Aarhus C, Denmark.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Division of Medical Genetics, Department of Biomedicine, University of Basel, Switzerland.|Institute of Human Genetics, Department of Genomics, Life & Brain Center, University of Bonn, Germany.|Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.affiliation: Center of Mental Health, Division of Molecular Psychiatry, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.affiliation: Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Domschke
authors.affiliation: Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reif
authors.affiliation: Department of Pharmacology, University of Würzburg, Würzburg, Germany.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Lohse
authors.affiliation: Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Deckert
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000379:Agoraphobia / Q000235:genetics; D000483:Alleles; D001008:Anxiety Disorders / Q000235:genetics*; D016022:Case-Control Studies; D015897:Comorbidity; D019295:Computational Biology; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D016014:Linear Models; D008156:Luciferases / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016584:Panic Disorder / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D020710:RGS Proteins / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D012307:Risk Factors
chemical_list: D020413:3' Untranslated Regions; C000604774:MIRN4717 microRNA, human; D035683:MicroRNAs; D020710:RGS Proteins; C087182:RGS2 protein, human; D008156:Luciferases
keywords: MIR4717; association; gene regulation; miRNA; panic disorder