Department of Epidemiology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
Department of Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Sci Rep. 2016 Jun 22;6:28387. doi: 10.1038/srep28387.
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(-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.
微小 RNA（miRNA）作为基因表达的关键转录后调控因子。miRNA 及其 miRNA 结合位点的遗传变异可能影响 miRNA 功能并导致疾病风险。在这里，我们使用最大的阿尔茨海默病（AD）全基因组关联研究，研究了 miRNA 相关序列中的变体在多大程度上可以构成与 AD 相关的功能变体的一部分。首先，在 237 个 miRNA 中的 237 个变体中，我们发现 miR-1229 前体中的 rs2291418 与 AD 显著相关（p 值=6.8×10(-5)，OR=1.2）。我们的计算机分析和体外 miRNA 表达实验表明，该变体的突变等位基因增强了 miR-1229-3p 的产生。接下来，我们发现与 AD 相关的 miR-1229-3p 靶基因可能介导 miRNA 功能。我们证明 miR-1229-3p 直接使用荧光素酶报告基因测定控制其顶级 AD 相关靶基因（SORL1）的表达。此外，我们表明 miR-1229-3p 和 SORL1 都在人脑表达。其次，在 miRNA 结合位点的 42,855 个变体中，我们确定了 10 个与 AD 显著相关的变体（9 个基因的 3'UTR 中），包括增加 miR-320e 对 PVRL2 调节的 rs6857。总的来说，这项研究表明 miRNA 相关变体与 AD 相关，并表明 miRNA 依赖的几个 AD 基因的调节。
