Genome-wide identification of microRNA-related variants associated with risk of Alzheimer’s disease
Ikram, M. Arfan
de Looper, Hans W. J.
Erkeland, Stefan J.
Franco, Oscar H.
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CitationGhanbari, Mohsen, M. Arfan Ikram, Hans W. J. de Looper, Albert Hofman, Stefan J. Erkeland, Oscar H. Franco, and Abbas Dehghan. 2016. “Genome-wide identification of microRNA-related variants associated with risk of Alzheimer’s disease.” Scientific Reports 6 (1): 28387. doi:10.1038/srep28387. http://dx.doi.org/10.1038/srep28387.
AbstractMicroRNAs (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 × 10−5, 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.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:27662241
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