儿童孤独症谱系障碍DLGAP1基因多态性研究

Role of disks large-associated protein 1 in autism spectrum disorders:a pilot study

目的分析Disks大同源物关联蛋白1(DLGAP1)基因在儿童孤独症谱系障碍(ASD)中的遗传多态性特征。方法上海交通大学医学院附属上海儿童医学中心2014年7月至2014年9月采用Affymetrix Cyto Scan基因芯片,对ASD儿童24例和非ASD儿童43例DLGAP1基因的297个单核苷酸多态性(SNP)进行病例-对照分析。两组资料进行多种模型(等位基因关联检验,基因型关联检验包括基因型模式、趋势模型、显性模型、隐性模型和Logistic回归)分析。结果 ASD组共发现20个有统计学意义的SNP。其中9个SNP在各模型中均有ASD发生风险,连锁不平衡分析显示rs9956191和rs4797127(D’=0.93,LOD=17.08,r^2=0.722)及rs4797180和rs8091193(D’=1.0,LOD=14.82,r^2=0.0933)呈强连锁不平衡。进一步的单体型分析表明,rs9956191/rs4797127(T-G)为ASD的发生风险(置换检验P=0.036)。该单体型是美国《精神障碍诊断与统计手册》第5版(DSM-Ⅴ)标准中社会情感互动缺陷,社交互动的非言语沟通行为缺陷,发展、维持和理解人际关系缺陷,刻板重复动作或语言,过分坚持常规或仪式化动作,过分狭窄或固定的兴趣6个条目发生风险因素,而不是感知觉异常的发生风险因素。结论 DLGAP1的遗传变异可能在ASD发病中具有一定作用。

Objective To investigate the features of genetic variants of disks large-associated protein 1（DLGAP1） gene for autism spectrum disorders（ASD） in a case control study. Methods Through Affymetrix cytoscan microarrays,297 single nucleotide polymorphisms（SNPs） covering the DLGAP1 gene were selected and analyzed in ASD patients（n=24） and non-ASD patients（n=43）. Results Twenty statistically significant SNPs with different inheritance models（Allelic Association test,Genotypic Association test including default model,genotypic model,trend model,dominant model,recessive model and Logistic regression） were demonstrated in case-control study. Associations of 9 SNPs with ASDs were significant in all models and strong linkage disequilibriums were found between rs9956191 and rs4797127（D’=0.93,LOD=17.08,r^2=0.722）and between rs4797180 and rs8091193（D’=1.0,LOD=14.82,r^2=0.0.933）.Further haplotype analysis showed that rs9956191/rs4797127（T-G）was statistically and significantly related to ASDs（Permutation,P=0.036）. The haplotype rs9956191/rs4797127（T-G）was significantly associated with the three items of social emotional field and three items of field for interest and stereotyped activities in DSM-V. No significant correlation of sensory perception with this haplotype was found. Conclusion These findings support that the genetic variants of DLGAP1 gene may play a role in ASD.