title: A GWAS SNP for Schizophrenia Is Linked to the Internal MIR137 Promoter and Supports Differential Allele-Specific Expression.
abstract: Single nucleotide polymorphisms (SNPs) within the MIR137 gene locus have been shown to confer risk for schizophrenia through genome-wide association studies (GWAS). The expression levels of microRNA-137 (miR-137) and its validated gene targets have also been shown to be disrupted in several neuropsychiatric conditions, including schizophrenia. Regulation of miR-137 expression is thus imperative for normal neuronal functioning. We previously characterized an internal promoter domain within the MIR137 gene that contained a variable number tandem repeat (VNTR) polymorphism and could alter the in vitro levels of miR-137 in a stimulus-induced and allele-specific manner. We now demonstrate that haplotype tagging-SNP analysis linked the rs1625579 GWAS SNP for schizophrenia to this internal MIR137 promoter through a proxy SNP rs2660304 located at this domain. We postulated that the rs2660304 promoter SNP may act as predisposing factor for schizophrenia through altering the levels of miR-137 expression in a genotype-dependent manner. Reporter gene analysis of the internal MIR137 promoter containing the common VNTR variant demonstrated genotype-dependent differences in promoter activity with respect to rs2660304. In line with previous reports, the major allele of the rs2660304 proxy SNP, which has previously been linked with schizophrenia risk through genetic association, resulted in downregulation of reporter gene expression in a tissue culture model. The genetic influence of the rs2660304 proxy SNP on the transcriptional activity of the internal MIR137 promoter, and thus the levels of miR-137 expression, therefore offers a distinct regulatory mechanism to explain the functional significance of the rs1625579 GWAS SNP for schizophrenia risk.
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, The University of Liverpool, Liverpool, UK;
authors.forename: Alix
authors.initials: A
authors.lastname: Warburton
authors.affiliation: MRC Social Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College London, London, UK; Biomedical Research Centre for Mental Health, South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, National Institute for Health Research (NIHR), King's College London, London, UK.
authors.forename: Gerome
authors.initials: G
authors.lastname: Breen
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, The University of Liverpool, Liverpool, UK;
authors.forename: Vivien J
authors.initials: VJ
authors.lastname: Bubb
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, The University of Liverpool, Liverpool, UK; jquinn@liverpool.ac.uk.
authors.forename: John P
authors.initials: JP
authors.lastname: Quinn
mesh_terms: D018929:Cell Culture Techniques; D005786:Gene Expression Regulation / Q000235:genetics*; D059647:Gene-Environment Interaction; D055106:Genome-Wide Association Study; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D018598:Minisatellite Repeats; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012559:Schizophrenia / Q000235:genetics*
chemical_list: C545567:MIRN137 microRNA, human; D035683:MicroRNAs
keywords: gene-environment interaction; linkage disequilibrium; microRNA-137; proxy SNP