【作者】 王佳；

【导师】 宋然然；

【作者基本信息】 华中科技大学 ， 儿少卫生与妇幼保健学， 2017， 硕士

【摘要】 目的:探讨影响突触信号传导的NRXN-NLGN-SHANK通路与儿童孤独症易感性的关系,为阐述孤独症的发病机制及实施干预治疗措施提供参考依据。方法:采用病例对照的研究方法,纳入研究529名孤独症儿童和1923名湖北省健康对照人群,选取纳入NRXN-NLGN-SHANK基因通路上的6个主要基因(NLGN1、NRXN1、NRXN2、NRXN3、PSD95、SHANK3)上10个功能性常见变异进行基因分型分析,通过拟合优度?~2检验判断基因型分布是否符合Hardy-Weinberg遗传平衡定律;用?~2检验判断病例组和对照组等位基因和基因型频率分布情况。采用非条件logistic回归进行基因多态性与孤独症之间的关联性分析和基因-基因交互作用分析,采用SPSS13.0和Stata11.0软件运行。结果:1.研究共包括529名孤独症儿童(平均年龄为8.24±3.16岁),1923名健康对照人群(平均年龄为61.38±8.51岁)。病例组与对照组性别比例匹配,男性与女性比7:1。2.非条件logistic回归分析的结果显示,NLGN1 rs9855544 A到G的突变和NRXN3 rs12879016 T到G的突变显著降低了孤独症的患病风险(OR=0.856,95%CI=0.746-0.981,P=0.025;OR=0.811,95%CI=0.699-0.941,P=0.006),NRXN2rs12273892 A到T的突变显著增加了孤独症的患病风险(OR=1.328,95%CI=1.133-1.557,P<0.001);对性别进行分层分析,探讨整体分析中三个阳性位点NLGN1 rs9855544,NRXN2 rs12273892,NRXN3 rs12879016在不同性别间的影响,结果发现在男性中rs9855544 A到G的突变和rs12879016 T到G的突变也同样降低了孤独症的患病风险(OR=0.849,95%CI=0.732-0.985,P=0.030;OR=0.790,95%CI=0.671-0.930,P=0.005),rs12273892 A到T的突变显著增加了男性孤独症的患病风险(OR=1.347,95%CI=1.134-1.600,P=0.001),但是这种影响在女性患者中并未发现。3.用logistic回归模型评估SNP-SNP之间潜在的相乘和相加交互作用。我们发现了rs9855544与rs12273892两位点的相乘交互作用接近统计学意义(P=0.066),分类的基因型相乘模型显示,与携带rs9855544 GG基因型和rs12273892 AA基因型的个体相比,携带rs9855544 AA+GA基因型和rs12273892 AA基因型的个体患孤独症的风险增加了0.711倍(OR=1.711,95%CI=1.162-2.520);携带rs9855544 GG基因型和rs12273892 TT+AT基因型的个体患孤独症的风险增加了1.507倍(OR=2.507,95%CI=1.553-4.047);携带rs9855544 AA+GA基因型和rs12273892 TT+AT基因型的个体患孤独症的风险增加了1.219倍(OR=2.219,95%CI=1.531-3.217)。其它位点之间的交互作用并未发现。结论:影响突触信号传导的NRXN-NLGN-SHANK基因通路上的NLGN1rs9855544,NRXN2 rs12273892,NRXN3 rs12879016位点的遗传变异与孤独症的发病风险显著相关,并且对男性的影响更明显。NLGN1 rs9855544和NRXN2rs12273892两位点可能存在显著的相乘交互作用,同时携带两位点的危险基因型会对孤独症的发病风险产生更显著的影响。更多还原

【Abstract】 Objective:To explore the association among gene polymorphisms of synaptic signal transduction pathway and autism susceptibility in Chinese children,which could provide more understanding of the pathogenesis of autism and scientific theory evidence for intervention and treatment measures.Methods:A case-control study was performed to analysis 529 autistic children and1923 healthy controls.Ten genetic variants in six main genes(NLGN1,NRXN1,NRXN2,NRXN3,PSD95 and SHANK3)on the NRXN-NLGN-SHANK pathway that affect synaptic signaling were genotyped.We used goodness-of-fitχ~2 test to assess the Hardy–Weinberg equilibrium for genotypes.The differences in distribution of genotype and allele frequencies between cases and controls were calculated by Pearson’sχ~2 test.The unconditional logistic regression was performed to examine the association between genes on NRXN-NLGN-SHANK pathway and autism susceptibility.Gene-gene interactions were examined using logistic regression in additive and multiplicative model.The statistical analyses were carried out with SPSS13.0 and Stata11.0 software.Results:1.The study included 529 children with autism(mean ages 8.24±3.16 years)and 1923 healthy controls(mean ages 61.38±8.51 years).The sex proportion of control was matched with case,and the radio of male and female was 7:1.2.The results of unconditional logistic regression analysis showed that the mutation of NLGN1 rs9855544 A to G and NRXN3 rs12879016 T to G mutation significantly reduced the risk of ASD(OR=0.856,95%CI=0.746-0.981,P=0.025;OR=0.811,95%CI=0.699-0.941,P=0.006)and the mutation of NRXN2 rs12273892 A to T significantly increased the risk of ASD(OR=1.328,95%CI=1.133-1.557,P<0.001).To explore the influences of the three positive loci NLGN1 rs9855544,NRXN2rs12273892,NRXN3 rs12879016 between different genders,we used gender stratification analysis.We found that mutation in rs9855544 A to G and rs12879016 T to G in male also reduced the risk of ASD(OR=0.849,95%CI=0.732-0.985,P=0.030;OR=0.790,95%OR=1.677-0.930,P=0.005).Rs12273892 A to T mutation significantly increased the risk of ASD(OR=1.347,95%CI=1.134-1.600,P=0.001),but this effects were not found in female patients.3.Logistic regression model was used to evaluate the potential multiplicative and additive interactions among SNPs.We found that the interaction between rs9855544and rs12273892 was close to statistical significance(P=0.066).The multiplicative genotype model showed that comparing with individuals carrying rs9855544 GG genotype and rs12273892 AA genotype,individuals carrying rs9855544 AA+GA genotype and rs12273892 AA genotype increased the risk of ASD by 0.711 times(OR=1.711,95%CI=1.162-2.520).The ASD risk of individuals carrying rs9855544GG genotype and rs12273892 TT+AT genotype was increased by 1.507 times(OR=2.507,95%CI=1.553-4.047);the risk of ASD with rs9855544 AA+GA genotype and rs12273892 TT+AT genotype increased by 1.219 times(OR=2.219,95%CI=1.531-3.217).The interaction between other SNPs was not found.Conclusion:The genetic variation of NLGN1 rs9855544,NRXN2 rs12273892 and NRXN3 rs12879016 on the NRXN-NLGN-SHANK pathway affecting synaptic signal transduction was significantly correlated with the risk of autism and the effect on male was more obvious.NLGN1 rs9855544 and NRXN2 rs12273892 have probably significant multiplicative interactions,and individuals carrying the risk genotype of two SNPs will have a more pronounced effect on the risk of ASD.更多还原