MicroRNA hsa-miR-4717-5p regulates RGS2 and may be a risk factor for anxiety-related traits

Leif Hommers*, Annette Raab, Alexandra Bohl, Heike Weber, Claus-Juergen Scholz, Angelika Erhardt, Elisabeth Binder, Volker Arolt, Alexander Gerlach, Andrew Gloster, Raffael Kalisch, Tilo Kircher, Tina Lonsdorf, Andreas Stroehle, Peter Zwanzger, Manuel Mattheisen, Sven Cichon, Klaus-Peter Lesch, Katharina Domschke, Andreas ReifMartin J. Lohse, Juergen Deckert

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

19 Citations (Web of Science)

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.? 2015
Original languageEnglish
Pages (from-to)296-306
JournalAmerican Journal of Medical Genetics Part B-neuropsychiatric Genetics
Volume168
Issue number4
DOIs
Publication statusPublished - Jun 2015

Keywords

  • miRNA
  • MIR4717
  • panic disorder
  • gene regulation
  • association

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