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.

Increased fear learning, spatial learning as well as neophobia in Rgs2−/− mice

“…) as well as dimensional measures of human anxiety (Hommers et al . ). However, results unable to replicate these findings were also reported (Hettema et al .…”

“…Treatment response to sertraline of patients suffering from social anxiety disorder was associated with RGS2 polymorphisms (Stein et al 2014). Moreover, microRNAs regulating RGS2 were associated with panic disorder (Muinos-Gimeno et al 2011) as well as dimensional measures of human anxiety (Hommers et al 2015). However, results unable to replicate these findings were also reported (Hettema et al 2013;Mouri et al 2010;Strug et al 2010), suggesting RGS2 to be one among several genes contributing to human anxiety.…”

The genetics of anxiety‐related negative valence system traits

“…One study reported association of CCKBR with AS and cholecystokinin‐induced panic [Koszycki et al, ]. A German PD research consortium reported association of AS with NPSR1 [Domschke et al, ], CRHR1 [Weber et al, ], and the gene coding for microRNA hsa‐miR‐4717‐5p, which regulates the gene RGS2 [Hommers et al, ], in conjunction with other PD‐related phenotypes. Such findings are tentative until adequately replicated.…”

Amygdalar expression of the microRNA miR‐101a and its target Ezh2 contribute to rodent anxiety‐like behaviour

“…miRNAs are increasingly recognized for their role in human mental illness (O'Connor et al ., ; Hauberg et al ., ). Single nucleotide polymorphisms associated with several miRNAs effect risk for anxiety disorders (Muinos‐Gimeno et al ., ; Hommers et al ., ), and expression levels of other miRNAs have been shown to correlate with anxiety symptoms (Xu et al ., ). Rodent studies show that acute and chronic stress affect miRNA expression (Meerson et al ., ; Rinaldi et al ., ), and rats that are vulnerable vs. resilient to developing learned helpless behaviour display baseline miRNA expression differences (Smalheiser et al ., ).…”