神经元迁移调控基因网络与汉语阅读障碍的相关研究

发布时间：2018-03-16 19:29

本文选题：汉语阅读障碍　切入点：社会经济地位　出处：《华中科技大学》2016年博士论文　论文类型：学位论文

【摘要】：本研究拟从流行病学特点、遗传因素以及环境与遗传的交互作用三个层次逐步探讨汉语阅读障碍的影响因素,为汉语阅读障碍的预防、诊断和干预提供理论依据。第一部分湖北省四市/县汉语阅读障碍儿童的流行病学调查及影响因素分析目的：了解湖北省汉语阅读障碍儿童的检出率及其分布特征,探索汉语阅读障碍的流行病学特点及影响因素。方法：采取整群抽样的方法,抽取湖北省四个市/县共46所小学的3-6年级全体学生为研究对象,进行问卷调查。共发放问卷25,150份,收回有效问卷19,844份。采用χ2检验和趋势检验进行数据分析。结果：汉语阅读障碍儿童的总检出率为3.6%,男生显著高于女生(χ2=254.02,P0.001)；χ2检验的结果显示,汉语阅读障碍儿童在反映社会经济地位的变量上(包括家庭成员平均月收入、父亲文化程度、母亲文化程度)和反映家庭阅读环境的变量上(包括儿童是否参加课外活动如阅读,儿童的自主学习习惯,儿童是否有固定阅读时间,父母阅读书籍的频率,父母给孩子购买书籍的间隔期,父母每年给孩子买书的花销,父母给孩子讲故事的频率,父母鼓励孩子看课外书籍的频率,父母买孩子喜欢书的频率)的分布差异均有显著性意义(χ2检验的P值均小于0.05)。趋势检验的结果进一步提示,社会经济地位越好,家庭阅读环境越好,儿童阅读障碍的检出率越低(趋势检验的P值均小于0.001)。结论：性别、家庭社会经济地位和家庭阅读环境是汉语阅读障碍发生的影响因素。第二部分神经元迁移调控网络基因变异与汉语阅读障碍易感性的关联研究目的：探讨神经元迁移调控网络上的基因变异与汉语阅读障碍易感性的关系,寻找影响汉语阅读障碍发生的遗传因素。方法：采用病例-对照的研究方法,从409名汉语阅读障碍组儿童和410名对照组儿童的口腔拭子中提取DNA,对神经元迁移调控网络中的6个关键基因(DYX1C1、DCDC2、K1AA0319、ROBO1、KIAA0319L和DOCK4)上的16个功能性常见变异进行基因分型,采用非条件logistic回归法、决策树分析法、累计效应分析法进行统计分析。结果：①单因素logistic回归法的结果显示,经错误发现率(False discovery rate, FDR)校正后,KIAA0319L rs28366021 G到A的突变显著降低了汉语阅读障碍的患病风险(OR=0.67,95% CI=0.51-0.89),K1AA0319 rs4504469C到T的突变和DOCK4 rs2074130 C到T的突变均显著增加了汉语阅读障碍的患病风险(OR=1.61,95% CI=1.17-2.20；OR=1.68,95% CI=1.20-2.35);②经决策树预测,DOCK4 rs2074130、KIAA0319 rs4504469、DCDC2rs2274305和KIAA0319L rs28366021之间可能存在交互作用；与危险性最低组(同时携带rs2074130 CC、rs4504469 CC和rs2274305 GG基因型)相比,同时携带rs2074130 CC、rs4504469 CT或TT和rs28366021 GG基因型的个体汉语阅读障碍的患病风险显著增加(OR=2.29,95% CI=1.39-3.77),而同时携带rs2074130 CT或TT和rs28366021 GG基因型的个体汉语阅读障碍的患病风险最高(OR=2.98,95% CI=1.87-4.75)：③对DOCK4 rs2074130、K1AA0319 rs4504469、DCDC2 rs2274305和K1AA0319L rs28366021的累计效应分析显示,与携带0-2个危险等位基因组相比,携带3-4个危险等位基因组和携带5-7个危险等位基因组均显著增加了汉语阅读障碍的患病风险(OR=1.60,95% CI=1.19-2.15；OR=2.74,95% CI=1.42-5.32)；趋势检验亦有统计学意义(P0.001)。结论:神经元迁移调控网络上的KIAA0319L rs28366021、KIAA0319rs4504469或DOCK4 rs2074130单位点变异与汉语阅读障碍的发病风险显著相关,DOCK4 rs2074130、KIAA0319 rs4504469、DCDC2 rs2274305和KIAA0319Lrs28366021多位点的交互作用和累积效应可能对汉语阅读障碍的发病风险产生更为显著的影响。第三部分家庭社会经济地位和家庭阅读环境与神经元迁移调控网络基因的交互作用在汉语阅读障碍发生中的初步探讨目的：在前两部分的基础上,进一步探讨影响汉语阅读障碍发生的环境与基因的交互作用。方法：采用病例-对照的研究设计和logistic回归法,分析家庭社会经济地位和家庭阅读环境与神经元迁移调控网络上的易感基因变异在汉语阅读障碍上的两两交互作用。结果：FDR校正前,在汉语阅读障碍的危险性上,父母文化程度与KIAA0319L rs28366021位点的基因型存在显著的交互作用(Pinteraction= 0.048),父母阅读书籍的频率与KIAA0319L rs28366021位点的基因型存在显著的交互作用(Pinteraction=0.023),且交互作用的模型均符合生物生态学模型。经FDR校正后,以上两个交互作用的P值均大于0.05。结论：在汉语阅读障碍的发生中,KIAA0319L rs28366021与父母文化程度和父母阅读书籍的频率之间可能存在交互作用,交互模型为生物生态学模型。但考虑到多重检验可能带来的假阳性,以上结果有待更大样本的验证。
[Abstract]:This paper from the epidemiological features, influencing factors of three levels of interaction of genetic factors and environmental and genetic probes into Chinese dyslexia, for the prevention of Chinese dyslexia, provide a theoretical basis for the diagnosis and intervention. The first part of the Hubei Province four City / county Chinese reading factors epidemiological investigation and analysis of influence of disorder in children Objective: to understand the Hubei Province Chinese dyslexic children the prevalence and distribution characteristics, epidemiological characteristics and related factors of Chinese dyslexia. Methods: by cluster sampling method, extraction of four cities in Hubei province / all the county a total of 46 primary school students of Grade 3-6 as the research object, carries on the questionnaire survey. A total of 25150 questionnaires. 19844 copies of valid questionnaires. Using the chi square test 2 test and trend data analysis. Results: Chinese dyslexic children total detection rate was 3.6%, the boys show The higher than girls (x 2=254.02, P0.001 x 2); the results showed that Chinese dyslexic children in reflecting the social economic status variables (including the average family income, father's education, mother's education level) and reflect the family reading environment variables (including children whether to participate in extracurricular activities such as reading, children independent learning habits, whether children have a fixed reading time, reading books, parents frequency, parents give their children buy books every year interval, parents give their children to buy books spending, parents give children to tell the story of the frequency, parents encourage their children to read the extracurricular books frequency, parents buy children love the book) has frequency distribution the difference was significant (x2 test of 2 P values were less than 0.05). Trend test results further suggest that the social economic status of family reading environment better, better, the detection rate of dyslexia in children The lower (trend test P values were less than 0.001). Conclusion: gender, family and social economic status of the family reading environment are risk factors of Chinese dyslexia. The second part of the neuronal migration Association of genetic regulatory networks to gene mutation and Chinese dyslexia: To investigate the relationship between neuronal migration gene mutation and Chinese dyslexia susceptibility regulation on the network, looking for genetic factors disorder of Chinese reading effect. Methods: a case-control study, DNA from disorder group children and 410 children in control group oral swabs from 409 Chinese reading, 6 key of neuronal migration in gene regulatory networks (DYX1C1, DCDC2, K1AA0319 ROBO1, KIAA0319L, and DOCK4) on the 16 functional common variants were genotyped using non conditional logistic regression, decision tree analysis, the cumulative effect analysis method Statistical analysis was performed. Results: the single factor Logistic regression analysis showed that the false discovery rate (False discovery rate FDR KIAA0319L rs28366021 G) after correction to A mutation significantly reduces the risk of dyslexia (OR=0.67,95% CI=0.51-0.89), the prevalence of K1AA0319 rs4504469C to T rs2074130 C mutation and DOCK4 to T the mutation significantly increased the risk of dyslexia in (OR=1.61,95% CI=1.17-2.20 OR=1.68,95%; CI=1.20-2.35); the decision tree prediction, DOCK4 rs2074130, KIAA0319 rs4504469, the possible interaction between DCDC2rs2274305 and KIAA0319L rs28366021; and the lowest risk group (rs2074130 CC rs4504469 CC with rs2274305, and GG genotype) compared with rs2074130 CC, a significant increase in the risk of individual Chinese rs4504469 CT or TT and rs28366021 disorder GG genotype prevalence (O reading R=2.29,95% CI=1.39-3.77), and the individual Chinese obstacles while carrying rs2074130 or TT CT and rs28366021 GG genotypes in reading the risk highest (OR=2.98,95% CI=1.87-4.75): the DOCK4 rs2074130, K1AA0319 rs4504469, DCDC2 rs2274305 and K1AA0319L rs28366021 cumulative effect analysis showed that compared with the 0-2 risk alleles, carrying 3-4 risk etc. a genome and carrying 5-7 risk allele significantly increased the risk of dyslexia (OR=1.60,95% CI=1.19-2.15; OR=2.74,95% CI=1.42-5.32 disease); trend test was also statistically significant (P0.001). Conclusion: the regulation of neuronal migration on the network KIAA0319L rs28366021, was significantly related to the risk of KIAA0319rs4504469 or DOCK4 rs2074130 point mutation and Chinese DOCK4 rs2074130 KIAA0319 dyslexia, rs4504469, DCDC2 rs2274305 and KIAA0319L The interaction of rs28366021 is more and the cumulative effect of risk of Chinese dyslexia has a more significant effect. The interaction of the third part of the family socioeconomic status and family reading environment and gene regulatory networks of neuronal migration disorders in the preliminary study in Chinese Reading: on the basis of the two parts, further study the interaction of environmental and genetic disorders of the Chinese reading effect. Methods: the study design and logistic regression method using case-control analysis, family socioeconomic status and family reading environment and regulation of neuronal migration network susceptible gene mutation in 22 interaction barriers on Chinese reading. Results: FDR before correction, in the risk of Chinese dyslexia, there was significant interaction between genotype KIAA0319L and parents'education locus rs28366021 ( Pinteraction= 0.048), there was significant interaction between genotype frequency and rs28366021 locus KIAA0319L parents read the books (Pinteraction=0.023), and the interaction model are consistent with the bio ecological model. After FDR correction, the above two interaction P values were greater than 0.05.. Conclusion: in the event of Chinese dyslexia, there may be the interaction between KIAA0319L rs28366021 and the cultural degree of parents and parents reading frequency, interaction model for biological ecology model. But considering multiple testing may bring false positive, the above results are to be confirmed with larger samples.

【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R749.94

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