title: Schizophrenia risk variants affecting microRNA function and site-specific regulation of NT5C2 by miR-206.
abstract: Despite the identification of numerous schizophrenia-associated genetic variants, few have been examined functionally to identify and characterize the causal variants. To mitigate this, we aimed at identifying functional variants affecting miRNA function. Using data from a large-scale genome-wide association study of schizophrenia, we looked for schizophrenia risk variants altering either miRNA binding sites, miRNA genes, promoters for miRNA genes, or variants that were expression quantitative trait loci (eQTLs) for miRNA genes. We hereby identified several potentially functional variants relating to miRNA function with our top finding being a schizophrenia protective allele that disrupts miR-206׳s binding to NT5C2 thus leading to increased expression of this gene. A subsequent experimental follow-up of the variant using a luciferase-based reporter assay confirmed that the allele disrupts the binding. Our study therefore suggests that miR-206 may contribute to schizophrenia risk through allele-dependent regulation of the genome-wide significant gene NT5C2.
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative of Integrative Psychiatric Research (iPSYCH), Denmark; Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark. Electronic address: hauberg@biomed.au.dk.
authors.forename: Mads Engel
authors.initials: ME
authors.lastname: Hauberg
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Marie Hebsgaard
authors.initials: MH
authors.lastname: Holm-Nielsen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative of Integrative Psychiatric Research (iPSYCH), Denmark; Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Anne Louise
authors.initials: AL
authors.lastname: Askou
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative of Integrative Psychiatric Research (iPSYCH), Denmark; Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark; Bioinformatics Research Centre (BiRC), Aarhus University, Aarhus, Denmark.
authors.forename: Jakob
authors.initials: J
authors.lastname: Grove
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative of Integrative Psychiatric Research (iPSYCH), Denmark; Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark.
authors.forename: Anders Dupont
authors.initials: AD
authors.lastname: Børglum
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark. Electronic address: corydon@biomed.au.dk.
authors.forename: Thomas Juhl
authors.initials: TJ
authors.lastname: Corydon
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D019295:Computational Biology; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D040641:Quantitative Trait Loci; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism*
chemical_list: C546087:MIRN206 microRNA, human; D035683:MicroRNAs; D015720:5'-Nucleotidase; C508048:NT5C2 protein, human
keywords: Genome-wide association study; MicroRNA; Schizophrenia; Single nucleotide polymorphism; and NT5C2; miR-206