PUB - Publikationen an der Universität Bielefeld

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 regulateRGS2were 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 ofRGS2. Hsa‐miR‐4717‐5p showed the most robust effect onRGS2and regulated two other candidate genes of anxiety disorders (CNR1andIKBKE) 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 (r² = 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 thatMIR4717regulates human RGS2 and contributes to the genetic risk towards anxiety‐related traits. © 2015 Wiley Periodicals, Inc.