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Genetic variation in the miR-708 gene and its binding targets in bipolar disorder.

ABSTRACT: OBJECTIVE:rs12576775 was found to be associated with bipolar disorder (BD) in a genome-wide association study (GWAS). The GWAS signal implicates genes for the microRNAs miR-708 and miR-5579 and the first exon of the Odd Oz/ten-m homolog 4 gene (ODZ4). In the present study, miR-708, its surrounding region, and its targets were analyzed for potential BD-associated functional variants. METHODS:The miR-708 gene and surrounding regions were screened for variation using high-resolution melting (HRM) analysis in 1099 cases of BD, followed by genotyping of rare variants in an enlarged sample of 2078 subjects with BD, 1303 subjects with schizophrenia, and 1355 healthy controls. Whole-genome sequencing data from 99 subjects with BD were analyzed for variation in potential miR-708 binding sites. The minor allele frequencies (MAFs) of these variants were compared with those reported in reference individuals. RESULTS:Three variants detected by HRM were selected to be genotyped. rs754333774 was detected in three cases of BD, two cases of schizophrenia, and no controls. This variant is located 260 base pairs upstream from miR-708 and may play a role in controlling the expression of the miR. Four variants were identified in miR-708 targets binding sites. The MAFs of each of these variants were similar in BD and reference samples. CONCLUSIONS:We report a single recurrent variant located near the miR-708 gene that may have a role in BD and schizophrenia susceptibility. These findings await replication in independent cohorts, as do functional analyses of the potential consequences of this variant.

SUBMITTER: Fiorentino A

PROVIDER: S-EPMC5244671 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Genetic variation in the miR-708 gene and its binding targets in bipolar disorder.

Fiorentino Alessia A O'Brien Niamh Louise NL Sharp Sally Isabel SI Curtis David D Bass Nicholas James NJ McQuillin Andrew A

Bipolar disorders 20161116 8

<h4>Objective</h4>rs12576775 was found to be associated with bipolar disorder (BD) in a genome-wide association study (GWAS). The GWAS signal implicates genes for the microRNAs miR-708 and miR-5579 and the first exon of the Odd Oz/ten-m homolog 4 gene (ODZ4). In the present study, miR-708, its surrounding region, and its targets were analyzed for potential BD-associated functional variants.<h4>Methods</h4>The miR-708 gene and surrounding regions were screened for variation using high-resolution ...[more]

PMID: 27864917

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Project description:Genetic variation in the cholinergic muscarinic-2 (M(2)) receptor gene (CHRM2) has been associated with the risk for developing depression. We previously reported that M(2)-receptor distribution volume (V(T)) was reduced in depressed subjects with bipolar disorder (BD) relative to depressed subjects with major depressive disorder (MDD) and healthy controls (HCs). In this study, we investigated the effects of six single-nucleotide polymorphisms (SNPs) for CHRM2 on M(2)-receptor binding to test the hypotheses that genetic variation in CHRM2 influences M(2)-receptor binding and that a CHRM2 polymorphism underlies the deficits in M(2)-receptor V(T) observed in BD. The M(2)-receptor V(T) was measured using positron emission tomography and [(18)F]FP-TZTP in unmedicated, depressed subjects with BD (n=16) or MDD (n=24) and HCs (n=25), and the effect of genotype on V(T) was assessed. In the controls, one SNP (with identifier rs324650, in which the ancestral allele adenine (A) is replaced with one or two copies of thymine (T), showed a significant allelic effect on V(T) in the pregenual and subgenual anterior cingulate cortices in the direction AA<AT<TT. In contrast, in BD subjects with the TT genotype, V(T) was significantly lower than in BD subjects with the AT genotype in these regions. The BD subjects homozygous for the T -allele also showed markedly lower V(T) (by 27 to 37% across regions) than HCs of the same genotype. Post hoc analyses suggested that T homozygosity was associated with a more severe illness course, as manifested by lower socioeconomic function, poorer spatial recognition memory and a greater likelihood of having attempted suicide. These data represent novel preliminary evidence that reduced M(2)-receptor V(T) in BD is associated with genetic variation within CHRM2. The differential impact of the M(2)-receptor polymorphism at rs324650 in the BD and HC samples suggests interactive effects with an unidentified vulnerability factor for BD.

Dataset Information

Genetic variation in the miR-708 gene and its binding targets in bipolar disorder.

Publications

Genetic variation in the miR-708 gene and its binding targets in bipolar disorder.

Similar Datasets

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