CNTNAP2、NRNX1、SHANK3多态性与汉族儿童孤独症的相关性研究
摘要
孤独症是一种广泛发育障碍性疾病,以社会交往障碍、语言发育障碍、兴趣狭窄和刻板重复的行为方式为基本临床特征。孤独症被认为是儿童广泛性发育障碍(Pervasive developmental disorder, PDD)的一个亚型。阿斯伯格综合征(Asperger disorder, AS)、广泛性发育障碍未注明(PDD not otherwise specified, PDD-NOS)和儿童瓦解性精神障碍具有相似的临床特征而被归类为孤独症谱群疾病(ASD),他们均属于儿童广泛性发育障碍疾病。孤独症的病因学复杂,包括了遗传和环境的因素的影响,双生子和家系研究的结果显示遗传因素在孤独症的致病中起了重要作用,孤独症的遗传度高达80-90%。在中国人群中,孤独症患病率高达0.11%,中国人口数高达13亿,孤独症患者给社会造成极大的负担。因此,研究中国汉族人群的孤独症的病因具有重要意义。而突触在神经系统中具有重要作用,与突触结构功能相关的基因CNTNAP2,NRXN1和SHANK3可能与中国汉族人群的孤独症的易感性相关,因此有必要研究这三个基因是否为汉族人的孤独症的易感基因。
方法：在采用芯片技术进行基因分型之前,我们采用PCR-RFLP技术对161个孤独症核心家系的CNTNAP2基因的三个SNPs位点进行了基因分型,并采用haploview4.1软件进行了家系为基础的传递不平衡检验。为进一步研究中国汉族儿童的CNTNAP2, NRXN1和SHANK3基因多态性与孤独症的相关性,采用Illumina CNV 370-Duo芯片对280个孤独症的核心家系人员,共455例孤独症患者及97例对照进行全基因组SNP分型。其余1000例对照来自安徽医科大学采用Illumina 610芯片进行基因分型的数据。从中选取CNTNAP2、NRXN1、SHANK3所有SNPs基因分型数据,采用haploview4.1软件进行家系为基础的传递不平衡检验和病例-对照关联分析,并分别构建单体型。
结果：1、家系为基础的传递不平衡检验和病例-对照研究的结果均显示CNTNAP2基因的rs7785603,rs10085579,rs2972110位点与孤独症显著关联,这几个SNPs的一些单体型与孤独症的易感性相关。
2、家系为基础的传递不平衡检验和病例-对照研究的结果均显示NRXN1基因的rs1518551,rs719645位点与孤独症显著关联,这几个SNPs的一些单体型与孤独症的易感性相关。
3、家系为基础的传递不平衡检验和病例-对照研究的结果均显示SHANK3基因的rs8137951位点与孤独症显著关联,Block 2的GA、AG单体型与孤独症的易感性相关。
结论：本研究结果显示CNTNAP2基因、NRXN1基因、SHANK3基因的遗传变异为中国汉族人孤独症的易感因素,研究结果支持CNTNAP2基因、NRXN1基因、SHANK3基因为孤独症易感基因。但考虑到孤独症这样的神经发育疾病的复杂性,及本研究相对较小的样本量和样本的遗传异质性,因此,有必要加大样本量对其进一步研究。
Autism is a pervasive developmental disorder mainly characterized by limited or absent verbal communication, lacking of reciprocal social interaction or responsiveness and restricted, stereotypical, and ritualized patterns of interests and behavior. Autism together with childhood disintegrative disorder, pervasive not otherwise specified (PDD-NOS, or atypical autism) and Asperger syndrome share the similar characteristics and are all included as autism spectrum disorder (ASD), also known as pervasive developmental disorder (PDD). The etiology is rather heterogeneous with the involvement of both genetic and nongenetic factors. Nevertheless, twin and family studies have indicated a primal role of genetic factors in the etiology of autism. In such studies, autism shows heritability as high as 80-90%. Autism was reported to affect approximately 0.11% of the population in China. Considering that the population is over 1.3 billion, autism presents a significant disease burden in China. Therefore, it is important to investigate the etiology of autism in the Chinese Han population. Synapses play an important role in the nervous system, the CNTNAP2, NRXN1 and SHANK3 related with the structure and function of synapses may be associated with autism that be demonstrated by some studies, so it is necessary to study the genes whether are autistic susceptible gene of the Chinese Han population.
Methods:Before the chip technology is used for genotyping, we genotyped the three SNPs of CNTNAP2 gene in 161 autistic trios by using PCR-RFLP technique, then a family-based transmission disequilibrium test is performed by using haploview4.1 software. Furthermore, attempt to investigate association of CNTNAP2, NRXN1 and SHANK3 polymorphisms with autism in Chinese Han children; genotyping was carried out by using Illumina CNV 370-Duo chip in 280 autistic trios,455 autistic children and 97 controls.1000 controls were genotyped by using Illumina 610 chip in the Anhui Medical University. The genotype data of CNTNAP2、NRXN1、SHANKS were selected. Family based association studies and case-control was performed by using haploview 4.1 and haplotypes were constructed respectively.
Results:1. The results of family association studies and case-control study showed that the rs7785603, rs10085579, rs2972110 of CNTNAP2 gene is associated with the increased risk for autism, and the haplotypes which included alleles of SNPs associated with autism also showed evidence of association.2. The results of family association studies and case-control study showed that the rs1518551, rs719645 of NRXN1 gene is associated with the increased risk for autism, and the haplotypes which included alleles of SNPs associated with autism also showed evidence of association.3. The results of family association studies and case-control study showed that the rs8137951 of SHANK3 gene is associated with the increased risk for autism, and haplotypes GA, AG of Block 2 also showed evidence of association.
Conclusion:
Our study showed that the genetic variability of CNTNAP2 gene, NRXN1 gene and SHANK3 gene are risk factors for autism in the Chinese Han population, which support the CNTNAP2 gene, NRXN1 gene and SHANK3 gene are susceptible gene of autism. Given the complex nature of a multifactorial neurodevelopmental disorders such as autism and the relatively small size of the study sample and their heterogeneity, further investigations, with larger sample size, are required to confirm whether the CNTNAP2 gene, NRXN1 gene and SHANK3 gene are associated with autism in the Chinese Han population.
方法：在采用芯片技术进行基因分型之前,我们采用PCR-RFLP技术对161个孤独症核心家系的CNTNAP2基因的三个SNPs位点进行了基因分型,并采用haploview4.1软件进行了家系为基础的传递不平衡检验。为进一步研究中国汉族儿童的CNTNAP2, NRXN1和SHANK3基因多态性与孤独症的相关性,采用Illumina CNV 370-Duo芯片对280个孤独症的核心家系人员,共455例孤独症患者及97例对照进行全基因组SNP分型。其余1000例对照来自安徽医科大学采用Illumina 610芯片进行基因分型的数据。从中选取CNTNAP2、NRXN1、SHANK3所有SNPs基因分型数据,采用haploview4.1软件进行家系为基础的传递不平衡检验和病例-对照关联分析,并分别构建单体型。
结果：1、家系为基础的传递不平衡检验和病例-对照研究的结果均显示CNTNAP2基因的rs7785603,rs10085579,rs2972110位点与孤独症显著关联,这几个SNPs的一些单体型与孤独症的易感性相关。
2、家系为基础的传递不平衡检验和病例-对照研究的结果均显示NRXN1基因的rs1518551,rs719645位点与孤独症显著关联,这几个SNPs的一些单体型与孤独症的易感性相关。
3、家系为基础的传递不平衡检验和病例-对照研究的结果均显示SHANK3基因的rs8137951位点与孤独症显著关联,Block 2的GA、AG单体型与孤独症的易感性相关。
结论：本研究结果显示CNTNAP2基因、NRXN1基因、SHANK3基因的遗传变异为中国汉族人孤独症的易感因素,研究结果支持CNTNAP2基因、NRXN1基因、SHANK3基因为孤独症易感基因。但考虑到孤独症这样的神经发育疾病的复杂性,及本研究相对较小的样本量和样本的遗传异质性,因此,有必要加大样本量对其进一步研究。
Autism is a pervasive developmental disorder mainly characterized by limited or absent verbal communication, lacking of reciprocal social interaction or responsiveness and restricted, stereotypical, and ritualized patterns of interests and behavior. Autism together with childhood disintegrative disorder, pervasive not otherwise specified (PDD-NOS, or atypical autism) and Asperger syndrome share the similar characteristics and are all included as autism spectrum disorder (ASD), also known as pervasive developmental disorder (PDD). The etiology is rather heterogeneous with the involvement of both genetic and nongenetic factors. Nevertheless, twin and family studies have indicated a primal role of genetic factors in the etiology of autism. In such studies, autism shows heritability as high as 80-90%. Autism was reported to affect approximately 0.11% of the population in China. Considering that the population is over 1.3 billion, autism presents a significant disease burden in China. Therefore, it is important to investigate the etiology of autism in the Chinese Han population. Synapses play an important role in the nervous system, the CNTNAP2, NRXN1 and SHANK3 related with the structure and function of synapses may be associated with autism that be demonstrated by some studies, so it is necessary to study the genes whether are autistic susceptible gene of the Chinese Han population.
Methods:Before the chip technology is used for genotyping, we genotyped the three SNPs of CNTNAP2 gene in 161 autistic trios by using PCR-RFLP technique, then a family-based transmission disequilibrium test is performed by using haploview4.1 software. Furthermore, attempt to investigate association of CNTNAP2, NRXN1 and SHANK3 polymorphisms with autism in Chinese Han children; genotyping was carried out by using Illumina CNV 370-Duo chip in 280 autistic trios,455 autistic children and 97 controls.1000 controls were genotyped by using Illumina 610 chip in the Anhui Medical University. The genotype data of CNTNAP2、NRXN1、SHANKS were selected. Family based association studies and case-control was performed by using haploview 4.1 and haplotypes were constructed respectively.
Results:1. The results of family association studies and case-control study showed that the rs7785603, rs10085579, rs2972110 of CNTNAP2 gene is associated with the increased risk for autism, and the haplotypes which included alleles of SNPs associated with autism also showed evidence of association.2. The results of family association studies and case-control study showed that the rs1518551, rs719645 of NRXN1 gene is associated with the increased risk for autism, and the haplotypes which included alleles of SNPs associated with autism also showed evidence of association.3. The results of family association studies and case-control study showed that the rs8137951 of SHANK3 gene is associated with the increased risk for autism, and haplotypes GA, AG of Block 2 also showed evidence of association.
Conclusion:
Our study showed that the genetic variability of CNTNAP2 gene, NRXN1 gene and SHANK3 gene are risk factors for autism in the Chinese Han population, which support the CNTNAP2 gene, NRXN1 gene and SHANK3 gene are susceptible gene of autism. Given the complex nature of a multifactorial neurodevelopmental disorders such as autism and the relatively small size of the study sample and their heterogeneity, further investigations, with larger sample size, are required to confirm whether the CNTNAP2 gene, NRXN1 gene and SHANK3 gene are associated with autism in the Chinese Han population.
引文
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