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

Sci Rep. 2016 Jun 22:6:28387. doi: 10.1038/srep28387.

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(-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Binding Sites
  • Brain / metabolism
  • Gene Expression Regulation
  • Genome-Wide Association Study
  • Humans
  • LDL-Receptor Related Proteins / genetics*
  • LDL-Receptor Related Proteins / metabolism
  • Membrane Transport Proteins / genetics*
  • Membrane Transport Proteins / metabolism
  • MicroRNAs / chemistry
  • MicroRNAs / genetics*
  • Nectins / genetics*
  • Nucleic Acid Conformation
  • Polymorphism, Single Nucleotide

Substances

  • 3' Untranslated Regions
  • LDL-Receptor Related Proteins
  • MIRN1229 microRNA, human
  • MIRN320 microRNA, human
  • Membrane Transport Proteins
  • MicroRNAs
  • NECTIN2 protein, human
  • Nectins
  • SORL1 protein, human