Investigation of the involvement of <i>MIR185</i> and its target genes in the development of schizophrenia

Forstner, Andreas J.; Basmanav, Fitnat Buket; Mattheisen, Manuel; Böhmer, Anne C.; Hollegaard, Mads Vilhelm; Janson, Esther; Strengman, Eric; Priebe, Lutz; Degenhardt, Franziska; Hoffmann, Per; Herms, Stefan; Maier, Wolfgang; Mößner, Rainald; Rujescu, Dan; Ophoff, Roel A.; Moebus, Susanne; Mortensen, Preben Bo; Børglum, Anders D.; Hougaard, David M.; Frank, Josef; Witt, Stephanie H.; Rietschel, Marcella; Zimmer, Andreas; Nöthen, Markus M.; Miró, Xavier; Cichon, Sven

doi:10.1503/jpn.130189

Cited by 23 publications

(20 citation statements)

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“…Further, the implication of miR-185-5p (22q11 microdeletion locus) and its targetome in schizophre- miR-29b-2-5p, miR-29b-3p, miR-29c-3p, miR-29c-5p, miR-33a-3p, miR-33a-5p, miR-33b-3p, miR-33b-5p, miR-130a-3p, miR-130a-5p, miR-137, miR-378i, miR-640, miR-1228-3p, miR-1228-5p, miR-1281, miR-1307-3p, miR-1307-5p, miR-2682-3p, miR-2682-5p, miR-3160-3p, miR-3160-3p, miR-3160-5p, miR-3160-5p, miR-3655, miR-4301, miR-4304 nia is in line with results from a previous study that used an earlier, overlapping version of the PGC GWAS. 47 Our study is not without limitations. Of particular concern are limitations pertaining to miRNA target prediction methods (eAppendix 2, eTable 1, eTable 5, and eTable 6 in the Supplement).…”

Section: Discussionmentioning

confidence: 84%

Analyzing the Role of MicroRNAs in Schizophrenia in the Context of Common Genetic Risk Variants

et al. 2016

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; for the Schizophrenia Working Group of the Psychiatric Genomics Consortium IMPORTANCE The recent implication of 108 genomic loci in schizophrenia marked a great advancement in our understanding of the disease. Against the background of its polygenic nature there is a necessity to identify how schizophrenia risk genes interplay. As regulators of gene expression, microRNAs (miRNAs) have repeatedly been implicated in schizophrenia etiology. It is therefore of interest to establish their role in the regulation of schizophrenia risk genes in disease-relevant biological processes. OBJECTIVE To examine the role of miRNAs in schizophrenia in the context of disease-associated genetic variation. DESIGN, SETTING, AND PARTICIPANTS The basis of this study was summary statistics from the largest schizophrenia genome-wide association study meta-analysis to date (83 550 individuals in a meta-analysis of 52 genome-wide association studies) completed in 2014 along with publicly available data for predicted miRNA targets. We examined whether schizophrenia risk genes were more likely to be regulated by miRNA. Further, we used gene set analyses to identify miRNAs that are regulators of schizophrenia risk genes. MAIN OUTCOMES AND MEASURES Results from association tests for miRNA targetomes and related analyses. RESULTS In line with previous studies, we found that similar to other complex traits, schizophrenia risk genes were more likely to be regulated by miRNAs (P < 2 × 10 −16). Further, the gene set analyses revealed several miRNAs regulating schizophrenia risk genes, with the strongest enrichment for targets of miR-9-5p (P = .0056 for enrichment among the top 1% most-associated single-nucleotide polymorphisms, corrected for multiple testing). It is further of note that MIR9-2 is located in a genomic region showing strong evidence for association with schizophrenia (P = 7.1 × 10 −8). The second and third strongest gene set signals were seen for the targets of miR-485-5p and miR-137, respectively. CONCLUSIONS AND RELEVANCE This study provides evidence for a role of miR-9-5p in the etiology of schizophrenia. Its implication is of particular interest as the functions of this neurodevelopmental miRNA tie in with established disease biology: it has a regulatory loop with the fragile X mental retardation homologue FXR1 and regulates dopamine D 2 receptor density.

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Section: Discussionmentioning

confidence: 84%

Analyzing the Role of MicroRNAs in Schizophrenia in the Context of Common Genetic Risk Variants

et al. 2016

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“…Research on the potential role of miRNAs in 22q11.2 del-associated neuropsychiatric disorders has primarily focused on analyzing the effects of DGCR8 on miRNA expression and behavior, which stands to reason considering the effect it has on miRNA biogenesis [ 31 , 48 , 117 ]. More recently, there have been studies showing the effects of specific miRNAs that map to the deleted region, most notably MIR-185 , which may influence neuronal function and synaptogenesis independently of DGCR8-mediated biogenesis [ 7 , 49 , 51 , 117 ]. Overall, the bioinformatics analysis of predicted targets of miRNAs that were found to be down-regulated in our 22q11.2 del samples, which included miR-185, is consistent with the mouse studies in that there was enrichment for genes involved in neuropsychiatric disorders, synaptogenesis and neuron projection.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to viewing the role of miRNAs in 22q11.2 del from the perspective of the downstream effects of DGCR8 , haploinsufficiency for individual miRNA genes that map to the deleted region have also been considered in disease pathogenesis. The most well-studied in this regard is MIR-185 , which has been found to target other SZ candidate genes and influence dendritic spine density in the hippocampus [ 49 , 50 ]. MicroRNA-185 and its targets are also enriched in synapses [ 7 , 49 , 51 ].…”

Section: Introductionmentioning

confidence: 99%

“…The most well-studied in this regard is MIR-185 , which has been found to target other SZ candidate genes and influence dendritic spine density in the hippocampus [ 49 , 50 ]. MicroRNA-185 and its targets are also enriched in synapses [ 7 , 49 , 51 ]. MicroRNA-185 also affects immune developmental pathways, which might contribute to the immunological deficits found in a subset of patients with 22q11.2 del [ 52 , 53 ].…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA Profiling of Neurons Generated Using Induced Pluripotent Stem Cells Derived from Patients with Schizophrenia and Schizoaffective Disorder, and 22q11.2 Del

et al. 2015

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We are using induced pluripotent stem cell (iPSC) technology to study neuropsychiatric disorders associated with 22q11.2 microdeletions (del), the most common known schizophrenia (SZ)-associated genetic factor. Several genes in the region have been implicated; a promising candidate is DGCR8, which codes for a protein involved in microRNA (miRNA) biogenesis. We carried out miRNA expression profiling (miRNA-seq) on neurons generated from iPSCs derived from controls and SZ patients with 22q11.2 del. Using thresholds of p<0.01 for nominal significance and 1.5-fold differences in expression, 45 differentially expressed miRNAs were detected (13 lower in SZ and 32 higher). Of these, 6 were significantly down-regulated in patients after correcting for genome wide significance (FDR<0.05), including 4 miRNAs that map to the 22q11.2 del region. In addition, a nominally significant increase in the expression of several miRNAs was found in the 22q11.2 neurons that were previously found to be differentially expressed in autopsy samples and peripheral blood in SZ and autism spectrum disorders (e.g., miR-34, miR-4449, miR-146b-3p, and miR-23a-5p). Pathway and function analysis of predicted mRNA targets of the differentially expressed miRNAs showed enrichment for genes involved in neurological disease and psychological disorders for both up and down regulated miRNAs. Our findings suggest that: i. neurons with 22q11.2 del recapitulate the miRNA expression patterns expected of 22q11.2 haploinsufficiency, ii. differentially expressed miRNAs previously identified using autopsy samples and peripheral cells, both of which have significant methodological problems, are indeed disrupted in neuropsychiatric disorders and likely have an underlying genetic basis.

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“…Several studies have investigated the role of single miRNAs in the development of psychiatric disorder, 30 , 31 , 32 including BD. 33 However, to our knowledge, no systematic, genome-wide analysis of miRNA-coding genes has yet been performed.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder

Forstner¹,

Hofmann²,

Maaser³

et al. 2015

Transl Psychiatry

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Bipolar disorder (BD) is a severe and highly heritable neuropsychiatric disorder with a lifetime prevalence of 1%. Molecular genetic studies have identified the first BD susceptibility genes. However, the disease pathways remain largely unknown. Accumulating evidence suggests that microRNAs, a class of small noncoding RNAs, contribute to basic mechanisms underlying brain development and plasticity, suggesting their possible involvement in the pathogenesis of several psychiatric disorders, including BD. In the present study, gene-based analyses were performed for all known autosomal microRNAs using the largest genome-wide association data set of BD to date (9747 patients and 14 278 controls). Associated and brain-expressed microRNAs were then investigated in target gene and pathway analyses. Functional analyses of miR-499 and miR-708 were performed in rat hippocampal neurons. Ninety-eight of the six hundred nine investigated microRNAs showed nominally significant P-values, suggesting that BD-associated microRNAs might be enriched within known microRNA loci. After correction for multiple testing, nine microRNAs showed a significant association with BD. The most promising were miR-499, miR-708 and miR-1908. Target gene and pathway analyses revealed 18 significant canonical pathways, including brain development and neuron projection. For miR-499, four Bonferroni-corrected significant target genes were identified, including the genome-wide risk gene for psychiatric disorder CACNB2. First results of functional analyses in rat hippocampal neurons neither revealed nor excluded a major contribution of miR-499 or miR-708 to dendritic spine morphogenesis. The present results suggest that research is warranted to elucidate the precise involvement of microRNAs and their downstream pathways in BD.

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Investigation of the involvement of MIR185 and its target genes in the development of schizophrenia

Cited by 23 publications

References 60 publications

Analyzing the Role of MicroRNAs in Schizophrenia in the Context of Common Genetic Risk Variants

Analyzing the Role of MicroRNAs in Schizophrenia in the Context of Common Genetic Risk Variants

MicroRNA Profiling of Neurons Generated Using Induced Pluripotent Stem Cells Derived from Patients with Schizophrenia and Schizoaffective Disorder, and 22q11.2 Del

Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder

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