title: Genome-wide identification of microRNA-related variants associated with risk of Alzheimer's disease.
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.
authors.affiliation: 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.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Ghanbari
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.|Department of Neurology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.|Department of Radiology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
authors.forename: M Arfan
authors.initials: MA
authors.lastname: Ikram
authors.affiliation: Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
authors.forename: Hans W J
authors.initials: HWJ
authors.lastname: de Looper
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Mass, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Immunology, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands.
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Erkeland
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
authors.forename: Oscar H
authors.initials: OH
authors.lastname: Franco
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
mesh_terms: D020413:3' Untranslated Regions; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics* / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D000075983:Nectins / Q000235:genetics*; D009690:Nucleic Acid Conformation; D020641:Polymorphism, Single Nucleotide
chemical_list: D020413:3' Untranslated Regions; D026502:LDL-Receptor Related Proteins; C000627191:MIRN1229 microRNA, human; C572916:MIRN320 microRNA, human; D026901:Membrane Transport Proteins; D035683:MicroRNAs; C000619011:NECTIN2 protein, human; D000075983:Nectins; C102582:SORL1 protein, human