title: Genetic Variants in MicroRNAs and Their Binding Sites Are Associated with the Risk of Parkinson Disease.
abstract: MicroRNAs (miRNAs) are small noncoding RNAs that serve as key regulators of gene expression. They have been shown to be involved in a wide range of biological processes including neurodegenerative diseases. Genetic variants in miRNAs or miRNA-binding sites on their target genes could affect miRNA function and contribute to disease risk. Here, we investigated the association of miRNA-related genetic variants with Parkinson disease (PD) using data from the largest GWAS on PD. Of 243 miRNA variants, we identified rs897984:T>C in miR-4519 (P value = 1.3×10(-5) and OR = 0.93) and rs11651671:A>G in miR-548at-5p (P value = 1.1×10(-6) and OR = 1.09) to be associated with PD. We showed that the variant's mutant alleles change the secondary structure and decrease expression level of their related miRNAs. Subsequently, we highlighted target genes that might mediate the effects of miR-4519 and miR-548at-5p on PD. Among them, we experimentally showed that NSF is a direct target of miR-4519. Furthermore, among 48,844 miRNA-binding site variants, we found 32 variants (within 13 genes) that are associated with PD. Four of the host genes, CTSB, STX1B, IGSF9B, and HSD3B7, had not previously been reported to be associated with PD. We provide evidence supporting the potential impact of the identified miRNA-binding site variants on miRNA-mediated regulation of their host genes.
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3000, CA, 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, Rotterdam, 3000, CA, The Netherlands.
authors.forename: Sirwan K L
authors.initials: SK
authors.lastname: Darweesh
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Cancer Institute, Rotterdam, 3000, CA, The Netherlands.
authors.forename: Hans W J
authors.initials: HW
authors.lastname: de Looper
authors.affiliation: Department of Immunology, MS Center ErasMS, Erasmus University Medical Center, Rotterdam, 3000, CA, The Netherlands.
authors.forename: Marvin M
authors.initials: MM
authors.lastname: van Luijn
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3000, CA, 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 Epidemiology, Erasmus University Medical Center, Rotterdam, 3000, CA, The Netherlands.
authors.forename: M Arfan
authors.initials: MA
authors.lastname: Ikram
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3000, CA, The Netherlands.
authors.forename: Oscar H
authors.initials: OH
authors.lastname: Franco
authors.affiliation: Department of Immunology, Erasmus University Medical Center, Rotterdam, 3000, CA, The Netherlands.
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Erkeland
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3000, CA, The Netherlands.
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
mesh_terms: D001665:Binding Sites; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics*
chemical_list: D035683:MicroRNAs
keywords: GWAS; Parkinson disease; miRNA variant; miRNA-binding site variant