Biomedical Sciences ETDs

Publication Date

12-1-2014

Abstract

The genetic basis of schizophrenia is still largely unknown. Recent evidence suggests that a microRNA (miRNA), miR-137 may be involved. The first large schizophrenia genome wide association (GWAS) study, published in 2011, identified a variant within the host gene of this miRNA (MIR-137) as the top association. Since then, further evidence for the potential influence of this miRNA within the disorder has accumulated. These studies used a variety of methods from GWAS to neuroimaging. However, few studies have evaluated the mechanism for the association of the MIR-137 variant, nor how alterations in the miRNA may have downstream effects on its targets and the function of these targets within biological pathways. We hypothesized that the target genes of miR-137 are involved in schizophrenia relevant pathways, such as those affecting neuronal development and plasticity, and that the MIR-137 risk-associated variant may lead to altered regulation of such pathways. We predict that variants within the targets of the miRNA may further alter target regulation. Here we completed the following three aims to determine the potential impact of dysregulation by this miRNA in schizophrenia. 1) We characterized the targets of the miRNA and the pathways over-representing these genes. 2) We determined the schizophrenia-risk association of these targets within these target enriched pathways. 3) We evaluated the influence of variants within target genes of an enriched pathway and the previously associated miR-137 host gene variant on structural gray matter. Our results suggest that the targets of this miRNA are indeed involved in pathways relevant to neuronal development and plasticity and thus the development of schizophrenia. The target genes within these pathways contain variants associated with schizophrenia that may disrupt regulation by the miRNA. Variants within targets of the PKA signaling pathway coupled with the MIR-137 variant may influence the development of gray matter within the occipital, temporal, and parietal lobe. Overall, our studies further suggest that this miRNA is influential in schizophrenia and provide a map for future studies to determine the effects of dysregulation by miR-137 in the disorder.

Keywords

miR-137, schizophrenia, miRNA

Sponsors

National Institutes of Health (NIH) and the Department of Energy (DOE)

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Perrone-Bizzozero, Nora

Second Advisor

Turner, Jessica

First Committee Member (Chair)

Calhoun, Vince

Second Committee Member

Bustillo, Juan

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