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Transcriptional targets of the schizophrenia risk gene MIR137.

ABSTRACT: Genome-wide association studies (GWAS) have strongly implicated MIR137 (the gene encoding the microRNA miR-137) in schizophrenia. A parsimonious hypothesis is that a pathway regulated by miR-137 is important in the etiology of schizophrenia. Full evaluation of this hypothesis requires more definitive knowledge about biological targets of miR-137, which is currently lacking. Our goals were to expand knowledge of the biology of miR-137 by identifying its empirical targets, and to test whether the resulting lists of direct and indirect targets were enriched for genes and pathways involved in risk for schizophrenia. We overexpressed miR-137 in a human neural stem cell line and analyzed gene expression changes at 24 and 48?h using RNA sequencing. Following miR-137 overexpression, 202 and 428 genes were differentially expressed after 24 and 48?h. Genes differentially expressed at 24?h were enriched for transcription factors and cell cycle genes, and differential expression at 48?h affected a wider variety of pathways. Pathways implicated in schizophrenia were upregulated in the 48?h findings (major histocompatibility complex, synapses, FMRP interacting RNAs and calcium channels). Critically, differentially expressed genes at 48?h were enriched for smaller association P-values in the largest published schizophrenia GWAS. This work provides empirical support for a role of miR-137 in the etiology of schizophrenia.

SUBMITTER: Collins AL

PROVIDER: S-EPMC4080323 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Transcriptional targets of the schizophrenia risk gene MIR137.

Collins A L AL Kim Y Y Bloom R J RJ Kelada S N SN Sethupathy P P Sullivan P F PF

Translational psychiatry 20140701

Genome-wide association studies (GWAS) have strongly implicated MIR137 (the gene encoding the microRNA miR-137) in schizophrenia. A parsimonious hypothesis is that a pathway regulated by miR-137 is important in the etiology of schizophrenia. Full evaluation of this hypothesis requires more definitive knowledge about biological targets of miR-137, which is currently lacking. Our goals were to expand knowledge of the biology of miR-137 by identifying its empirical targets, and to test whether the ...[more]

PMID: 24984191

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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).

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Transcriptional targets of the schizophrenia risk gene MIR137.

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Transcriptional targets of the schizophrenia risk gene MIR137.

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