摘要
儿童孤独症(Autism, MIM 209850)是一种以社会交往和语言沟通障碍、刻板行为及兴趣范围狭窄为主要特征的儿童广泛性发育障碍；也是最常见的儿童精神疾病之一,世界范围内的发病率约为1-6‰。近年来相关研究已揭示了若干孤独症的易感位点和基因,但其主要易感基因尚不明确。基于家系的连锁分析揭示了多个与孤独症相关的染色体区域,其中染色体7q是得到最多重复验证、并被荟萃分析证实的孤独症易感位点,称为AUST1。该区域内有一些基因被作为重要的孤独症候选基因开展相关性研究,如RELN、MET、FOXP2、CNTNAP2、EN2基因等；目前对于这些基因的研究结论并不一致,有待进一步阐明位于该区域内的重要孤独症易感基因。
本研究以中国汉族儿童孤独症患者为研究对象(共455名患者,所有患者均根据DSM-IV标准作出诊断并签署知情同意书,同时选用1097名中国汉族正常人作为对照),用Illumina Human CNV-370基因芯片进行基因分型,对孤独症候选基因开展病例-对照关联研究。在本研究中,分析了位于染色体7q、通过连锁分析获得最高重复性的3个区域：7q22、7q31和7q35-qter;在以上区域中挑选了10个基因(NPTX2、LRRN3、GPR85、FOXP2、MET、ST7、WNT2、GRM8、EN2和CNPY1基因)作为孤独症候选基因进行分析。
通过对中国汉族儿童孤独症患者的病例-对照研究发现4个基因存在与孤独症显著相关的位点,它们分别是MET基因(rs2237712,x2=5.845,p=0.0156；rs2237713，x2=6.1,p=0.0135),ST7基因(rs7788320,x22=5.037,p=0.0248；rs7785492，x22=4.341,p=0.0372),EN2基因(rs1861958,x22=4.341,p=0.0372)和GRM8基因(rs2108849，x2=4.92,p=0.0266；rsl419472，x2=4.12,p=0.0424；rsll563410，x2=6.573,p=0.0104；rsll56653，x2=4.181,p=0.0409；rs2283089，x2=4.377,p=0.0364)。此外,本课题组的前期研究还证实了位于染色体7q35-36的CNTNAP2基因也与中国汉族儿童孤独症显著相关。综上所述,MET、ST7、GRM8、EN2和CNTNAP2基因可能是位于染色体7q的重要孤独症易感基因。
精神分裂症(Schizophrenia, MIM 181500)是一种最常见的精神疾病,以基本个性的改变,思维、情感、行为的分裂,精神活动与环境不协调为主要特征。全世界平均患病率约为1%。研究表明：精神分裂症属于多基因遗传病,1p、1 q、4p、6p、7q、8p、13q、22q等若干染色体区域可能存在精神分裂症易感位点(基因)。
人类RELN(Reelin)基因位于染色体7q22,编码一个由3461个氨基酸组成的分泌型糖蛋白,在胚胎发育时期参与神经元迁移和大脑皮层、海马、小脑等高度层状结构形成的重要发育过程中,在成年人中枢神经系统调控突触可塑性。精神分裂症、双相情感障碍、孤独症和无脑回畸形等患者死后的尸检均发现脑部RELN基因表达量显著降低；有研究者提出该基因与多种精神疾病(如精神分裂症、抑郁症、双相情感障碍以及孤独症)的发病机制均相关。分子遗传学研究提供了RELN基因可能是精神分裂症易感基因的证据,但在中国人群中尚无相关报道。
本研究以中国汉族精神分裂症家系为研究对象(包括44个家系,共计244名家系成员,其中104人被确诊为精神分裂症患者；所有诊断均由相关临床医师根据DSM-IV标准作出)。通过TaqMan-PCR法对位于RELN基因内部的2个SNPs位点(rs2229864和rs736707)进行基因分型,采用家系内传递不平衡检验开展RELN基因多态性与中国汉族人群精神分裂症的关联研究。结果显示：在精神分裂症家系中,SNP-rs2229864的C等位基因频率分布存在显著差异(χ2=7.049,p=0.0079),rs2229864-rs736707组成的单倍型“TT”传递与未传递的比例存在显著差异(x2=7.438,p=0.0064)。本研究表明：RELN基因可能与中国汉族人群精神分裂症发生相关,该基因可能是一个精神分裂症的易感基因。
Autism (MIM 209850) is characterized by delayed language development, trouble with social interactions, stereotyped behaviors and interested in a very narrow range of things, which categorize to pervasive developmental disorders. Autism is the most common childhood psychiatric disorders, and its worldwide prevenlance is about 1-6‰.
In recent years, researchers has revealed a number of autism susceptibility loci and genes, but the major susceptibility gene is still unclearly. Family-based linkage analysis has revealed several regions associated with autism, of which the chromosome 7q, also known as AUST1, is the most replicated autism susceptibility locus and was also confirmed by meta-analysis. Some genes within this region, such as RELN, MET, FOXP2, CNTNAP2 and EN2 genes has been evident to be candidate genes of autism by association-study, though results of previously study is contradictory. In this study, we are intent to clarify which are the most importance autism susceptibility genes located in the chromosome 7q.
In total of 455 Chinese Han patients with autism was employed in this study, all of which were diagnosed according to DSM-IV and signed informed consent. And we also recruited 1097 Chinese Han people as control. Illumina Human CNV-370 microarray was used to genotype all the candidate genes and case-control association study was performed. There are 3 regions in chromosome 7q gained highest repeatability by linkage analysis:7q22,7q31, and 7q35-qter; So we selected 10 candidate genes (NPTX2、LRRN3、GPR85、FOXP2、MET、ST7、WNT2、GRM8、EN2 and CNPY1gene) in the above regions for analysis.
Our results indicated that 4 genes were significantly associated with autism, which are the MET gene (rs2237712,χ2=5.845, p=0.0156; rs2237713,χ2=6.1, p=0.0135), ST7 gene (rs7788320,χ2=5.037, p=0.0248; rs7785492,χ2=4.341, p=0.0372), EN2 gene (rs1861958, x2=4.341, p =0.0372) and GRM8 gene (rs2108849,χ2=4.92, p=0.0266; rs1419472, =4.12, p=0.0424; rs11563410,χ2=6.573, p=0.0104; rs1156653,χ2= p=0.0409; rs2283089,χ2=4.377, p=0.0364). In addition, previous studies in our lab has confirmed that CNTNAP2 gene,which located in 7q35-36 are also significantly associated with Chinese Han autistic children. In summary, MET, ST7, GRM8, EN2 and CNTNAP2 gene may be the important autism susceptibility genes which located on chromosome 7q.
Schizophrenia (MIM 181500) is one of the most common mental illnesses. It is a severe psychiatric disorder characterized by loss of contact with reality (psychosis), hallucinations, delusions, distorted thinking, strange feelings, diminished motivation and various cognitive impairments that disturbed work and social functioning. Worldwidely, about 1%of the population is affected by schizophrenia. It is a complex, multifactorial disorder that occuring involved of multiple genes and environmental factors. Several schizophrenia susceptibility locus have been mapped to 1p, 1q,4p,6p,7q,8p,13q,22q and many other chromosomal regions, and it is supposed that many genes predisposing to schizophrenia.
Human RELN (Reelin) gene located on chromosome 7q22, which encodes a 3461Aa secreted glycoprotein that is essential for neuronal ventrcular migration to form a highly laminated structures in the cerebral cortex, hippocampus and cerebellum during the embryonic CNS development, and it also play important roles in regulating synaptic plasticity throughout the adult CNS. In post-mortem study of schizophrenia, bipolar, autism and lissencephaly individuals showed a significantly decrease of RELN expression in the brain. Researchers raiesd the hypothesis that maybe RELN gene is involved in the pathogenesis of a variety of psychiatric disorders, such as schizophrenia, depression, bipolar disorders and autism. Previously association study indicated that RELN gene maybe one of the susceptibility genes of schizophrenia, but there is no evidences for the correlation of RELN gene and the Chinese Schizophrenia patients.
In total of 44 Han Chinese Schizophrenia families was employed in this study, including 244 family members, of which 104 were diagnosed to be schizophrenia according to DSM-IV criteria. There are 2 SNPs within the RELN gene, rs2229864 and rs736707, was genotyping by TaqMan-PCR method and then analyzed by transmission disequilibrium test (TDT). Accroding to our results, the frequency of SNP-rs2229864 C-allele were significantly different between the schizophrenia pedigrees and normal control (x2=7.049, p=0.0079), so did the "TT" haplotype of rs2229864-rs736707 (x2=7.438, p=0.0064). This study shows that RELN gene maybe associated with schizophrenia in Chinese Han population and it is possible to be a schizophrenia susceptibility gene.
引文
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