Warburton Alix, Breen Gerome, Bubb Vivien J, Quinn John P
Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, The University of Liverpool, Liverpool, UK;
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.
Schizophr Bull. 2016 Jul;42(4):1003-8. doi: 10.1093/schbul/sbv144. Epub 2015 Oct 1.
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.
通过全基因组关联研究（GWAS）已表明，MIR137基因座内的单核苷酸多态性（SNP）会增加患精神分裂症的风险。在包括精神分裂症在内的几种神经精神疾病中，microRNA - 137（miR - 137）及其已验证的基因靶点的表达水平也被证明受到破坏。因此，miR - 137表达的调节对于正常神经元功能至关重要。我们之前鉴定了MIR137基因内的一个内部启动子结构域，该结构域包含一个可变数目串联重复序列（VNTR）多态性，并且能够以刺激诱导和等位基因特异性的方式改变miR - 137的体外水平。我们现在证明，单倍型标签SNP分析通过位于该结构域的一个代理SNP rs2660304，将精神分裂症的rs1625579 GWAS SNP与这个MIR137内部启动子联系起来。我们推测，rs2660304启动子SNP可能通过以基因型依赖的方式改变miR - 137的表达水平，而成为精神分裂症的一个易感因素。对包含常见VNTR变体的MIR137内部启动子进行的报告基因分析表明，就rs2660304而言，启动子活性存在基因型依赖性差异。与之前的报告一致，rs2660304代理SNP的主要等位基因先前已通过遗传关联与精神分裂症风险相关联，在组织培养模型中导致报告基因表达下调。因此rs2660304代理SNP对MIR137内部启动子转录活性以及miR - 137表达水平的遗传影响，提供了一种独特的调节机制来解释rs1625579 GWAS SNP对精神分裂症风险的功能意义。
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