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首页> 外文学位 >Imprinting in the schizophrenia-associated gene GABRB2 encoding GABAA receptor beta2 subunit.
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Imprinting in the schizophrenia-associated gene GABRB2 encoding GABAA receptor beta2 subunit.

机译：印在精神分裂症相关基因GABRB2编码GABAA受体beta2亚基。

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摘要

Schizophrenia is a complex genetic disorder, the inheritance pattern of which is likely complicated by epigenetic factors yet to be elucidated. In the present study, single nucleotide polymorphisms (SNPs) in the GABA A receptor beta2 subunit gene (GABRB2) were found to be associated with schizophrenia but not Alzheimer's disease. In addition, transmission disequilibrium tests with family trios yielded significant differences between paternal and maternal transmissions of the schizophrenia-associated SNP rs6556547 and its haplotypes. The minor allele (T) of rs6556547 was paternally undertransmitted to male schizophrenic offsprings, and this parent-of-origin effect (POE) strongly suggested that GABRB2 is imprinted. 'Flipping' of allelic expression in heterozygotes of SNP rs2229944 (C/T) in GABRB2, or rs2290732 (G/A) in the neighbouring GABRA1 was compatible with imprinting effects on gene expression. Clustering analysis of GABRB2 mRNA expressions suggested that imprinting brought about the observed two-tiered distribution of expression levels in controls with heterozygous genotype at the schizophrenia-associated SNP rs1816071 (A/G). The deficit of upper-tiered expressions accounted for the lowered expression levels in the schizophrenic heterozygotes. The occurrence of a two-tiered distribution furnished support for imprinting, and also pointed to the necessity of differentiating between two kinds of heterozygotes of different parental origins in disease association studies on GABRB2. Bisulphite sequencing revealed hyper-methylation in the neighbourhood of SNP rs1816071, and methylation differences between controls and schizophrenia patients. Notably, the two schizophrenia-associated SNPs rs6556547 and rs1816071 overlapped with a CpG dinucleotide, thereby opening the possibility that CpG methylation status of these sites could modulate the risk of schizophrenia. Thus multiple lines of evidence pointed to the occurrence of imprinting in the GABRB2 gene and its possible role in the development of schizophrenia.
机译：精神分裂症是一种复杂的遗传性疾病，其遗传模式很可能会受到尚待阐明的表观遗传因素的影响。在本研究中，发现GABA A受体beta2亚基基因（GABRB2）中的单核苷酸多态性（SNP）与精神分裂症有关，但与阿尔茨海默氏病无关。此外，与家庭三重奏的传播不平衡测试在精神分裂症相关SNP rs6556547的父本和母本传播及其单倍型之间产生了显着差异。 rs6556547的次要等位基因（T）在父系中未充分传播给男性精神分裂症后代，这种起源祖母效应（POE）强烈暗示了GABRB2的印记。 GABRB2的SNP rs2229944（C / T）或邻近的GABRA1的rs2290732（G / A）的杂合子中等位基因表达的“翻转”与基因表达的印迹作用兼容。 GABRB2 mRNA表达的聚类分析表明，印记导致在精神分裂症相关SNP rs1816071（A / G）具有杂合基因型的对照中观察到表达水平的两层分布。精神分裂症杂合子中较低水平的表达导致了较低的表达水平。两层分布的出现为印迹提供了支持，并且还指出了在GABRB2疾病关联研究中区分不同亲本来源的两种杂合子的必要性。亚硫酸氢盐测序显示SNP rs1816071附近存在高度甲基化，而对照组和精神分裂症患者之间的甲基化差异。值得注意的是，两个与精神分裂症相关的SNP rs6556547和rs1816071与CpG二核苷酸重叠，从而打开了这些位点的CpG甲基化状态可能调节精神分裂症风险的可能性。因此，多种证据表明在GABRB2基因中存在印迹并在精神分裂症的发展中可能发挥作用。

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  • 作者

    Pun, Wing Frank.;

  • 作者单位

    Hong Kong University of Science and Technology (Hong Kong).;

  • 授予单位 Hong Kong University of Science and Technology (Hong Kong).;
  • 学科 Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 112 p.
  • 总页数 112
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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