title: Allele-specific regulation of DISC1 expression by miR-135b-5p.
abstract: Disrupted-in-schizophrenia-1 (DISC1) gene has been established as a risk factor for various neuropsychiatric phenotypes. Both coding and regulatory variants in DISC1 have been identified and associated with these phenotypes in genetic studies. MicroRNAs (miRNAs) are important regulators of protein coding genes. Since the miRNA-mRNA target recognition mechanism is vulnerable to disruption by DNA polymorphisms, we investigated whether polymorphisms in the DISC1 3'UTR affect binding of miRNAs and lead to allele-specific regulation of DISC1. We identified four predicted polymorphic miRNA target sites in the DISC1 3'UTR, and demonstrated that miR-135b-5p regulates the level of DISC1 mRNA. Moreover, DISC1 regulation by miR-135b-5p is allele specific: miR-135b-5p only binds to the major allele (A) of rs11122396, not to the minor allele (G). Thus, the G allele may be functionally related to the DISC1-associated phenotypes by abolishing regulation by miR-135b-5p, leading to elevated DISC1 levels.
authors.affiliation: 1] Institute for Molecular Medicine, Finland (FIMM), University of Helsinki, Helsinki, Finland [2] Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Mari
authors.initials: M
authors.lastname: Rossi
authors.affiliation: 1] Institute for Molecular Medicine, Finland (FIMM), University of Helsinki, Helsinki, Finland [2] The Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Helena
authors.initials: H
authors.lastname: Kilpinen
authors.affiliation: 1] Institute for Molecular Medicine, Finland (FIMM), University of Helsinki, Helsinki, Finland [2] Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Muona
authors.affiliation: 1] Institute for Molecular Medicine, Finland (FIMM), University of Helsinki, Helsinki, Finland [2] Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Ida
authors.initials: I
authors.lastname: Surakka
authors.affiliation: The Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ingle
authors.affiliation: 1] Department of Biosciences, Viikki Biocenter, University of Helsinki, Helsinki, Finland [2] Research Programs Unit, Biomedicum-Helsinki, and Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Jenni
authors.initials: J
authors.lastname: Lahtinen
authors.affiliation: 1] Institute for Molecular Medicine, Finland (FIMM), University of Helsinki, Helsinki, Finland [2] Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: William
authors.initials: W
authors.lastname: Hennah
authors.affiliation: 1] Institute for Molecular Medicine, Finland (FIMM), University of Helsinki, Helsinki, Finland [2] Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland [3] The Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
authors.affiliation: 1] Institute for Molecular Medicine, Finland (FIMM), University of Helsinki, Helsinki, Finland [2] Department of Biosciences, Viikki Biocenter, University of Helsinki, Helsinki, Finland [3] Research Programs Unit, Biomedicum-Helsinki, and Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland [4] Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Iiris
authors.initials: I
authors.lastname: Hovatta
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000483:Alleles; D001665:Binding Sites / Q000235:genetics; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D016014:Linear Models; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D020413:3' Untranslated Regions; C412476:DISC1 protein, human; C544965:MIRN135 microRNA, human; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D008156:Luciferases