Genome-wide identification of microRNA-related variants associated with risk of Alzheimer's disease

Ghanbari, M. and Ikram, M. A. and De Looper, H. W. J. and Hofman, A. and Erkeland, S. J. and Franco, O. H. and Dehghan, A. (2016) Genome-wide identification of microRNA-related variants associated with risk of Alzheimer's disease. Scientific Reports, 6.

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Abstract

MicroRNAs (miRNAs) serve as key post-Transcriptional regulators of gene expression. Genetic variation in miRNAs and miRNA-binding sites may affect miRNA function and contribute to disease risk. Here, we investigated the extent to which variants within miRNA-related sequences could constitute a part of the functional variants involved in developing Alzheimer's disease (AD), using the largest available genome-wide association study of AD. First, among 237 variants in miRNAs, we found rs2291418 in the miR-1229 precursor to be significantly associated with AD (p-value = 6.8 × 10 â '5, OR = 1.2). Our in-silico analysis and in-vitro miRNA expression experiments demonstrated that the variant's mutant allele enhances the production of miR-1229-3p. Next, we found miR-1229-3p target genes that are associated with AD and might mediate the miRNA function. We demonstrated that miR-1229-3p directly controls the expression of its top AD-Associated target gene (SORL1) using luciferase reporter assays. Additionally, we showed that miR-1229-3p and SORL1 are both expressed in the human brain. Second, among 42,855 variants in miRNA-binding sites, we identified 10 variants (in the 3′ UTR of 9 genes) that are significantly associated with AD, including rs6857 that increases the miR-320e-mediated regulation of PVRL2. Collectively, this study shows that miRNA-related variants are associated with AD and suggests miRNA-dependent regulation of several AD genes.

Item Type: Article
Additional Information: Cited By :18 Export Date: 16 February 2020 Correspondence Address: Ghanbari, M.; Department of Epidemiology, Erasmus University Medical CenterNetherlands; email: m.ghanbari@erasmusmc.nl
Uncontrolled Keywords: carrier protein low density lipoprotein receptor related protein microRNA MIRN320 microRNA, human nectin NECTIN2 protein, human SORL1 protein, human 3' untranslated region Alzheimer disease binding site brain chemistry conformation gene expression regulation genetics genome-wide association study human metabolism single nucleotide polymorphism 3' Untranslated Regions Binding Sites Humans LDL-Receptor Related Proteins Membrane Transport Proteins MicroRNAs Nectins Nucleic Acid Conformation Polymorphism, Single Nucleotide
Subjects: WM Psychiatry
QZ pathology-neoplasms-Genetics
Divisions: Mashhad University of Medical Sciences
Depositing User: mr lib4 lib4
Date Deposited: 02 Mar 2020 09:21
Last Modified: 02 Mar 2020 09:21
URI: http://eprints.mums.ac.ir/id/eprint/12994

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