汉语阅读障碍与言语／语言发育相关疾病共享候选基因的关联研究

Dyslexia, as the most common type of learning disabilities, is a persistent neurodevelopmental disorder. In recent years, the data from large databases have showed overlapping causation of psychiatric disorders with shared genetic risk variants. Speech/language development is closely related to reading ability. Speech-sound disorder, specific language impairment and dyslexia display high comorbidity. Thus, it is speculated that genetic loci involved in speech-sound disorder and specific language impairment may also influence the risk of dyslexia. In this study, we intend to carry out the following researches: (1) The potentially functional loci of 6 susceptibility genes (CMIP, ATP2C2, FOXP1, FOXP2, CNTNAP2 and TPK1) for speech-sound disorder and specific language impairment will be predicted by bioinformatics analyses. (2) A case-control study will be conducted in a population enrolled from Shenzhen city to investigate the association between dyslexia susceptibility and the above potentially functional loci. (3) In-depth molecular biological experiments will be performed to explore the mechanism underlying the positive associations. This study will provide a new strategy to elucidate the cause of dyslexia. Besides, the functional variants revealed by current study can be applied as genetic markers for individual risk assessment and early screening for Chinese dyslexia.

阅读障碍是学习障碍的主要类型，是一种长期持续存在的神经发育障碍性疾病。近年来基于大数据的研究结果表明，神经精神疾病往往存在重叠的致病机制而表现出共享遗传危险因素。儿童言语/语言的发展与阅读能力密切相关，语音障碍和特发性语言障碍常常共患阅读障碍，因此推测其遗传变异同样影响阅读障碍的发病风险。本课题拟在前期工作的基础上开展以下研究：（1）应用生物信息学预测筛选语音障碍、特发性语言障碍易感基因CMIP、ATP2C2、FOXP1、FOXP2、CNTNAP2和TPK1的潜在功能性遗传位点；（2）在深圳地区开展病例-对照研究，探讨上述候选位点与阅读障碍易感性之间的关系；（3）采用一系列功能实验深入揭示汉语阅读障碍相关阳性位点的分子生物学功能。本课题将为当前阅读障碍研究领域提供新的思路和策略，所识别和验证的疾病相关遗传变异可望用于个体风险评估和早期筛查。

儿童言语/语言的发展与阅读能力的获得密切相关，言语/语言发育相关疾病常常共患阅读障碍，从而推测影响言语/语言发育的环境因素和遗传因素同样影响阅读障碍的发病风险。本课题采用病例-对照研究探讨家庭结构、家庭生育小孩个数和出生次序、小孩3岁前父母是否在外地工作、小孩3岁前的主要照看者、父母亲每日与孩子相处的平均时间、家庭常用语言种类等因素及语音障碍、特发性语言障碍易感基因CMIP、ATP2C2、FOXP1、FOXP2、CNTNAP2和TPK1的16个潜在功能性位点与汉语阅读障碍的关联，结果显示增加母亲每天与儿童的相处时间可降低阅读障碍发病风险。此外，CMIP基因rs4548853位点三种基因型在病例组和对照组儿童中的分布具有统计学差异，然而经错误发现率（FDR）多重校正后，差异不再具有统计学意义。CMIP基因rs4548853位点与rs2530位点存在相乘交互作用和相加交互作用；TPK1基因rs2371641位点与ATP2C2基因rs4782969位点存在相乘交互作用，经FDR多重校正后以上交互作用仍具有统计学意义。本课题为阅读障碍研究领域提供新的思路和策略，所识别的疾病相关环境和遗传因素对于阐明阅读障碍的病因机制提供了一定的理论依据。