X染色体失活的统计度量及合并X染色体失活与印记效应的关联分析研究

X chromosome inactivation (XCI) is the phenomenon that only one of two copies of X chromosome in females, during early embryonic development, is expressed to achieve the dose compensation of X-linked genes between males and females, which is stated to be related to genomic imprinting. It has been shown in literature that the genetic mechanism of many complex diseases is associated with the inactivated X-linked genes and imprinting effects. Currently, there have been several studies which incorporate the XCI into association analysis. However, they do not take account of imprinting effects, which is not matched with the inheritance of X chromosome. Nowadays, there are still the following unsolved but important issues and challenges. First, how to measure the degree of XCI and how to estimate this measure? Second, based on the additive genetic model, how to incorporate both the XCI and genetic imprinting into association study on X chromosome to improve the test power? Third, for the model-free case, how to develop the X-chromosome association study with the XCI and genetic imprinting? Therefore, in this project, we will first find a statistical method to estimate the degree of the XCI. Next, based on the additive genetic model, we will take account of the XCI and imprinting and propose a method to test for association between the genes on X chromosome and the diseases. Finally, we will suggest a method to detect the X-chromosome association by accounting for the XCI and imprinting, which is robust to various genetic models. To this connection, the issues considered in this project would provide both theoretical support and useful statistical tools for fine mapping on X chromosome.

人类X染色体失活是指女性胚胎发育早期两条X染色体中只表达其中一条以保证X连锁基因在两性间达到剂量平衡的现象，其还涉及基因组印记。研究表明，很多遗传病的发病机理跟X连锁基因失活及印记效应密切相关。目前，虽然已有一些关联分析方法研究X染色体失活对X伴性遗传病的影响，但均未合并印记效应的信息，这与X染色体的遗传机制不符，存在以下尚未解决的重要问题与难题：如何用统计指标度量X染色体失活的程度？基于加性遗传模型，如何将X染色体失活与印记效应合并到X染色体上的关联分析之中以提高其检验效能？如何建立对遗传模型不做限制的合并X染色体失活与印记效应的关联分析方法？因此，本项目将建立度量X染色体失活程度的统计指标；提出基于加性模型合并X染色体失活与印记效应的关联分析方法；建立对各种遗传模型均比较稳健的合并X染色体失活与印记效应的关联分析方法，为遗传流行病学中更加精准地定位X连锁基因提供理论支持和有效统计工具。

X染色体失活(XCI)是指女性胚胎发育早期两条X染色体中只表达其中一条以保证X连锁基因在两性间达到剂量平衡的现象，其还涉及印记效应。研究表明，很多遗传病的发病机理跟X连锁基因失活及印记效应密切相关。目前，虽然已有一些关联分析方法研究XCI对X伴性遗传病的影响，但均未合并印记效应的信息，这与X染色体的遗传机制不符。另外，目前尚未有统计指标用于度量XCI的程度。因此，本项目对现存问题进行研究，取得了如下创新性成果：提出度量XCI程度的统计指标；提出基于加性模型合并XCI与印记效应的关联分析方法；提出对各种遗传模型均稳健的合并XCI与印记效应的关联分析方法。以上成果均是首次报道，将其开发为R语言软件，为遗传流行病学中更加精准地定位X连锁基因提供理论支持和有效的统计分析工具。将这些软件运用到行为抑制解除疾病数据、类风湿关节炎数据以及Graves疾病数据，结果如下：位点rs5904577和rs5974270与行为抑制解除综合评分相关联；rs6530179与酒精依赖综合评分相关联；rs5949324与违禁药物综合评分相关联；rs6530179和rs2304605与尼古丁综合评分相关联，其中rs2304605位于FRMPD4基因内，FRMPD4被发现与智力发育障碍、非综合征X伴性智力障碍等疾病有关；rs792959同时跟违禁药物综合评分与行为抑制解除综合评分相关联，该位点上100%的细胞保持等位基因G的活性；rs12687163和rs12688347与行为抑制解除相关联，且它们均属于RPGR基因，该基因与细胞的化学信号通路有关，现有研究表明该基因突变会导致视网膜色素变性、听力丧失和上呼吸道感染等疾病；rs704833、rs1863548和rs11067062上的变异对酒精依赖综合评分有母源印记效应；rs6837925、rs4141854、rs9394515和rs4711553上的变异对酒精依赖综合评分有父源印记效应；rs12960235和rs715351上的变异对酒精消费综合评分有父源印记效应；rs2238907与类风湿关节炎相关联，在该位点上17.5%的细胞保持风险等位基因的活性，其余82.5%的细胞保持正常等位基因的活性；GPR174基因中的rs3827440位点跟Graves疾病相关联，该位点上68.7%的细胞保持风险基因T的活性，其余31.3%的细胞保持正常基因C的活性。

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