基于家系连锁分析和高通量测序结果的原发性闭角型青光眼的稀有变异负荷研究

primary angle closure glaucoma (PACG) is the leading cause of irreversible blindness in China, at the same time, it is a complex genetic disease, crowded ocular anatomical structure is the susceptible factor of the disease. The genome-wide association analysis was conducted in a large sample of sporadic PACG population through international cooperation for our research group in the early stage, and 9 susceptibility loci had been first reported in the world, however the mutation frequency of the corresponding candidate genes was low. Recent studies have shown that the effects of rare variants on the susceptibility to common diseases have moderate to strong effects, it can explain a large part of the missing heritability. In order to improve the detection efficiency, our research group had collected 59 PACG families from the same region and the whole genome linkage analysis and whole exome sequencing had been conducted. We intend to analysis the preliminary data by means of the rare variants burden analysis to ascertain the disease candidate gene, then validate the genes in the PACG pedigrees and sporadic PACG patients through exon sequencing of candidate genes. Next, the gene expression of the target tissue should be observed in the cadaver eyes and PACG eyes to help identify susceptibility gene finally. At last, the genotype-phenotype correlation analysis should be performed to guide the etiological typing. It will lay the foundation for future disease gene detection.

原发性闭角型青光眼（闭青）是中国人首要不可逆性致盲眼病，同时也是一种复杂遗传病，眼球解剖结构拥挤是疾病易感的前提。课题组前期通过国际合作开展了大样本散发闭青人群的全基因组关联分析，在国际上首次报道了9个疾病易感位点，但对应的候选基因在患病人群中突变率较低。最新研究表明稀有变异对常见疾病易患性有中到强度的效应影响，可解释很大部分的遗传缺失。为提高检出效能，课题组前期收集了59个来自同一地域的闭青家系，开展了全基因组连锁分析及全基因组外显子测序分析。本课题拟通过稀有变异负荷分析对前期数据进行研究，初步锁定疾病候选基因并在新的疾病家系、散发群体和正常对照中进行候选基因的外显子捕获测序验证，接下来在尸眼和患者眼部靶组织中进行初步表达研究，确定闭青易感基因，最后进行基因型-表型关联分析，用以指导疾病的病因学分型，为未来闭青基因预警检测打下基础。

原发性闭角型青光眼（闭青）是中国人首要不可逆性致盲眼病，同时也是一种复杂遗传病，患者具有特征性的眼球解剖参数易感性。课题组前期开展了大样本散发闭青人群的全基因组关联分析，在国际上首次报道了9个疾病易感位点，但对应的候选基因在患病人群中突变率较低。为发现更多与疾病密切关联的易感基因，课题组建立了大规模的中国人闭青及正常对照个体的DNA样本库和临床数据库。对59个来自同一地域的闭青遗传家系，开展了全基因组连锁分析及全基因组外显子测序研究，并对结果进行了多模式分析，包括稀有变异负荷分析，通路富集分析及数量性状位点分析。将候选基因在中国北方的400例闭青家族史阳性个体和400例中国北方正常对照个体中进行了二阶段验证分析。初步锁定了与不同解剖参数相关的染色体位点，其中晶体厚度、前房深度、眼轴的相关数量性状调控位点分别定位于1p36、3q28和13q13；闭青易感基因富集的通路有细胞外基质受体相互作用通路、局部粘附通路、蛋白消化和吸收通路等，其中局部粘附通路与课题组前期的研究结果相吻合；初步锁定闭青致病/易感基因7个。未来，这些致病/易感基因将在更大规模的散发闭青群体中进行验证研究，相关发现将为中国人闭青的疾病基因预警和基因分型提供重要依据，以实现早诊断、早预防、早治疗和降低疾病致盲率的最终目标。

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