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Free keywords:
miRNA, MIR4717, panic disorder, gene regulation, association
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. (c) 2015 Wiley Periodicals,
Inc.
