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.

Additional Metadata
Persistent URL dx.doi.org/10.1038/srep28387, hdl.handle.net/1765/96675
Journal Scientific Reports
Citation
Ghanbari, M, Ikram, M.K, de Looper, H, Hofman, A, Erkeland, S.J, Franco, O.H, & Dehghan, A. (2016). Genome-wide identification of microRNA-related variants associated with risk of Alzheimer's disease. Scientific Reports, 6. doi:10.1038/srep28387