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TCF4 与精神分裂症之间的关联并非通过常见的非同义突变或影响成人大脑中 mRNA 表达的顺式作用调控来发挥作用。

Association between TCF4 and schizophrenia does not exert its effect by common nonsynonymous variation or by influencing cis-acting regulation of mRNA expression in adult human brain.

机构信息

MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, UK.

出版信息

Am J Med Genet B Neuropsychiatr Genet. 2011 Dec;156B(7):781-4. doi: 10.1002/ajmg.b.31219. Epub 2011 Aug 2.

Abstract

Large collaborative Genome-wide Association studies of schizophrenia have identified genes and genomic regions that are associated with the disorder at highly stringent levels of statistical significance. Among these, transcription factor 4 (TCF4) is one of the best supported although the associated SNP (rs9960767) is located within intron 3 and has no obvious function. Seeking the mechanism at TCF responsible for the association, we examined TCF4 for coding variants, and for cis regulated variation in TCF4 gene expression correlated with the associated SNP using an assay to detect differential allelic expression. Using data from the 1000 genomes project, we were unable to identify any nonsynonymous coding variants at the locus. Allele specific expression analysis using human post mortem brain samples revealed no evidence for cis-regulated mRNA expression related to genotype at the schizophrenia associated SNP. We conclude that association between schizophrenia and TCF4 is not mediated by a relatively common non-synonymous variant, or by a variant that alters mRNA expression as measured in adult human brain. It remains possible that the risk allele at this locus exerts effects on expression exclusively in a developmental context, in cell types or brain regions not adequately represented in our analysis, or through post-transcriptional effects, for example in the abundance of the protein or its sub-cellular distribution.

摘要

大规模的精神分裂症全基因组关联研究已经确定了与该疾病相关的基因和基因组区域,这些区域在统计学上具有高度显著的关联。在这些区域中,转录因子 4(TCF4)是最受支持的区域之一,尽管相关的 SNP(rs9960767)位于内含子 3 中,没有明显的功能。为了寻找与该关联相关的 TCF 机制,我们检查了 TCF4 的编码变异,以及与相关 SNP 相关的 TCF4 基因表达的顺式调控变异,使用检测差异等位基因表达的检测方法。使用来自 1000 个基因组计划的数据,我们无法在该基因座鉴定出任何非同义编码变异。使用人类死后脑组织样本进行的等位基因特异性表达分析并未发现与与精神分裂症相关 SNP 相关的基因型相关的顺式调节 mRNA 表达的证据。我们得出结论,精神分裂症与 TCF4 之间的关联不是由相对常见的非同义变异或改变 mRNA 表达的变异介导的,如在成人脑中测量的那样。该基因座的风险等位基因可能仅在发育环境中、在我们的分析中未充分代表的细胞类型或脑区,或通过转录后效应,例如在蛋白质的丰度或其亚细胞分布中发挥作用,仍然是可能的。

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