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Novel brain expressed RNA identified at the MIR137 schizophrenia-associated locus.

ABSTRACT: Genome-wide association studies (GWAS) have identified a locus on chromosome 1p21.3 to be highly associated with schizophrenia. A microRNA, MIR137, within this locus has been proposed as the gene causally associated with schizophrenia, due to its known role as a regulator of neuronal development and function. However, the involvement of other genes within this region, including DPYD (dihydropyrimidine dehydrogenase), is also plausible. In this communication, we describe a previously uncharacterised, brain-expressed RNA, EU358092, within the schizophrenia-associated region at 1p21.3. As we observed for MIR137, EU358092 expression was modulated in response to psychoactive drug treatment in the human SH-SY5Y neuroblastoma cell line. Bioinformatic analysis of publically available CNS expression data indicates that MIR137 and EU358092 are often co-expressed in vivo. A potential regulatory domain for expression of EU358092 is identified by bioinformatic analysis and its regulatory function is confirmed by reporter gene assays. These data suggest a potentially important role for EU358092 in the aetiology of schizophrenia, either individually or in combination with other genes at this locus.

SUBMITTER: Gianfrancesco O

PROVIDER: S-EPMC5477099 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Novel brain expressed RNA identified at the MIR137 schizophrenia-associated locus.

Gianfrancesco Olympia O Warburton Alix A Collier David A DA Bubb Vivien J VJ Quinn John P JP

Schizophrenia research 20161129

Genome-wide association studies (GWAS) have identified a locus on chromosome 1p21.3 to be highly associated with schizophrenia. A microRNA, MIR137, within this locus has been proposed as the gene causally associated with schizophrenia, due to its known role as a regulator of neuronal development and function. However, the involvement of other genes within this region, including DPYD (dihydropyrimidine dehydrogenase), is also plausible. In this communication, we describe a previously uncharacteri ...[more]

PMID: 27913161

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Project description:Abstract Background It is well known that heritability plays a prominent role in risk for schizophrenia, and that this brain disorder is crucially characterized by emotional symptoms. Less known is how heritability shapes brain activity during emotion processing and whether this brain phenotype is also associated with genetic variation increasing risk for schizophrenia. Here, we implemented a multi-step, data-driven approach in order to assess the relevance of the link between heritability, genetic variation, and schizophrenia for brain activity during emotion processing. Methods We investigated three samples of healthy individuals and one sample of schizophrenia (SCZ) patients: i) 28 healthy twin pairs (16 monozygotic and 12 dizygotic twin pairs); ii) 289 unrelated healthy participants (genome-wide association study - GWAS -discovery sample); iii) 90 unrelated healthy participants (replication sample); iv) 40 SCZ patients. During fMRI, participants approached or avoided threatening angry faces (explicit emotion processing). Intra-class correlations (ICC) between twin pairs and ACE models (A: additive genetics; C: common environment; E: unique environment) were used to identify regions of interest (ROIs) with heritable functional activity. Then, we extracted BOLD signal from these ROIs and conducted a GWAS on 565,137 single nucleotide polymorphisms (SNPs) (selected with the following criteria: minor allele frequency>0.15, Hardy–Weinberg equilibrium<0.001, linkage disequilibrium pruning r2>0.9) using robust linear models of allelic dosage corrected for multiple comparisons (Gao et al. 2008 Genetic Epidemiology). Finally, we assessed the effect of surviving SNPs in the replication sample of healthy individuals as well as in the sample of SCZ patients. Results In healthy twins, we identified bilateral amygdala as the brain region with the highest heritability during explicit emotion processing as evaluated with our task (ICC=.79; h2=0.54; p<.001). The subsequent GWAS in healthy non-twins indicated that bilateral amygdala activity during the task was associated with a polymorphism close to miR-137 (rs1198575) (p=1.5 × 10–7), with the C allele corresponding to lower activity than the t allele. A similar effect was found in the replication sample (p=.01) and in patients with SCZ (p=.03). Discussion Our data-driven approach revealed that amygdala activity as evaluated with our task is heritable. Furthermore, our results indicate that a polymorphism in miR-137 has genome wide association with amygdala response during emotion processing which is also replicated in two independent samples of healthy subjects and of patients with schizophrenia. Previous findings indicated that this polymorphism has genome-wide association with schizophrenia (Ripke et al. 2014). Other results reveal that miR-137 is a key regulatory neuronal factor linked to SCZ and involved in emotion processing (Cosgrove et al., 2017). Our findings are consistent with these previous findings and further highlight a crucial role for miR-137 in emotion processing and SCZ (Anticevic et al., 2012 Schizophr Bull).

Project description:BackgroundProtein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors. Indeed, the growing understanding of the regulatory properties and pleiotropic effects that miRNA have on molecular and cellular mechanisms, suggests that alterations in the interactions between miRNAs and their mRNA targets may contribute to phenotypic variation.Methodology/principal findingsWe have studied the association between schizophrenia and genetic variants of miRNA genes associated with brain-expression using a case-control study design on three Scandinavian samples. Eighteen known SNPs within or near brain-expressed miRNAs in three samples (Danish, Swedish and Norwegian: 420/163/257 schizophrenia patients and 1006/177/293 control subjects), were analyzed. Subsequently, joint analysis of the three samples was performed on SNPs showing marginal association. Two SNPs rs17578796 and rs1700 in hsa-mir-206 (mir-206) and hsa-mit-198 (mir-198) showed nominal significant allelic association to schizophrenia in the Danish and Norwegian sample respectively (P = 0.0021 & p = 0.038), of which only rs17578796 was significant in the joint sample. In-silico analysis revealed that 8 of the 15 genes predicted to be regulated by both mir-206 and mir-198, are transcriptional targets or interaction partners of the JUN, ATF2 and TAF1 connected in a tight network. JUN and two of the miRNA targets (CCND2 and PTPN1) in the network have previously been associated with schizophrenia.Conclusions/significanceWe found nominal association between brain-expressed miRNAs and schizophrenia for rs17578796 and rs1700 located in mir-206 and mir-198 respectively. These two miRNAs have a surprising large number (15) of targets in common, eight of which are also connected by the same transcription factors.

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Novel brain expressed RNA identified at the MIR137 schizophrenia-associated locus.

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Novel brain expressed RNA identified at the MIR137 schizophrenia-associated locus.

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