儿童孤独症的全基因组关联研究

发布时间：2018-05-16 22:03

本文选题：孤独症 + 全基因组关联研究　；参考：《中南大学》2013年博士论文

【摘要】：儿童孤独症是一种严重影响儿童健康,并且具有高度临床和遗传异质性的神经发育障碍性疾病。孤独症患病率近年急剧上升,美国政府公布的最新数据显示,每50个儿童中就有一个患有孤独症。按照目前全球普遍的发病率估算,我国的孤独症患者已达一千多万。已有病因学研究发现,遗传和环境因素均参与孤独症的发生,且遗传因素在孤独症的病因中占主要作用,其遗传度高达90%。罕见或新发变异,如染色体异常,新发和罕见的拷贝数变异以及新发和罕见的单核苷酸变异和小的插入／缺失变异均被发现参与孤独症的遗传病因。通过罕见变异研究已经发现了多个孤独症相关的位点／区间和易感或致病基因。尽管如此,这些新发或罕见的孤独症遗传病因只能解释一小部分病人,绝大多数孤独症的遗传病因仍然未知。孤独症是一个涉及环境和遗传病因的复杂疾病,多个常见变异或常见变异与环境风险因素共同或交互作用被认为在孤独症病因中起到重要作用。与孤独症的新发和罕见遗传变异研究相比,通过全基因组关联研究发现的常见变异还比较少,目前只发现CDH9-CDH10, SEMA5A以及MACROD2几个基因或位点。我们认为多个常见变异共同或通过与环境相互作用会导致孤独症的发生,是孤独症可能的病因之一。基于这一假设,本研究进行了中国人群孤独症患者的全基因组关联研究。我们收集了两个样本组,一组为由患者和父母亲组成的核心家系(Triads)样本组,另一组为由散发病例和正常对照组成的病例-对照(Case-Control)样本组。我们对两组样本分别进行全基因组关联研究并做META分析,META分析的结果在三个欧美人群中进行验证,并对5个样本组进行META分析。五个样本组META分析得到的全基因组显著关联的结果在正常人和孤独症患者的脑基因表达数据中进行表达定量形状位点分析和基因差异表达分析。我们的研究结果显示中国人群两个样本组的全基因组关联研究结果均未发现全基因组显著相关位点。对两个样本组的结果进行结合分析发现在染色体1p13.2位点约400kb的连锁不平衡区间内有多个SNPs接近全基因组显著性相关水平。两个中国人群样本与3个欧美人群样本的META分析显示,1p13.2区间内的3个SNPs达到了全基因组显著性水平(rs936938:p=4.49×10-8; rs6537835:p=3.26×10-8; rs1877455:p=8.70×10-8)。对该区间的单体型分析发现,该3个全基因组显著性相关的SNPs分别位于3个与孤独症存在全基因组显著关联的单体型(AMPD1-NRAS-CSDE1:rs926938|rs8453|rs10489525; TRI M33:rs6537825|rs11582563|rs11585926|rs11589568|rs7511633|rs6661053|rs11102800|rs3827735|rs11102807;TRIM33-BCAS2:rs10858047|rs11587400|rs1877455)。表达定量性状位点分析发现全基因组显著相关的3个单体型内的多个SNPs影响到了CSDE1, NRAS以及TRIM33在人脑前额皮层中mRNA的表达水平,基因差异表达分析也发现TRIM33, NRAS, BCAS2以及CSDE1和在孤独症和正常人脑前额皮层和／或颞叶皮层中存在表达差异。我们的研究发现染色体1p13.2位点的3个单体型及其相关变异与孤独症的发病风险相关。表达定量性状位点和基因差异表达分析提示CSDE1, NRAS和TRIM33可能是孤独症的易感基因。本研究提示常见变异在孤独症发生中起到一定作用,多个常见变异共同或与环境因素相互作用可能是孤独症发生的病因之一。
[Abstract]:Autism is a neurodevelopmental disorder that seriously affects children's health and has a highly clinical and genetic heterogeneity. The prevalence of autism has risen sharply in recent years. The latest data published by the US government show that one in every 50 children is autistic. Patients with solitary disease have reached about ten million. Genetic and environmental factors have been found to be involved in autism, and genetic factors play a major role in the etiology of autism. The heritability is as high as 90%. rare or new mutations, such as chromosomal abnormalities, new and rare copy number variations, and new and rare single nucleotide changes. Different and small insertion / deletion mutations were found to be involved in the genetic cause of autism. Multiple autism related sites / intervals and susceptibility or pathogenic genes have been found through rare variations. However, the genetic causes of these new or rare autism can only explain a small number of patients and the inheritance of the vast majority of autism. The cause of the disease is still unknown.
Autism is a complex disease involving environmental and genetic causes. The common or interactive effects of multiple or common variation and environmental risk factors are considered to play an important role in the cause of autism. Compared with the new and rare genetic variation of autism, the common variations found through the whole genome association study are also compared. We have found only a few genes or loci of CDH9-CDH10, SEMA5A and MACROD2. We think that multiple common mutations Co or interaction with the environment can lead to autism, which is one of the possible causes of autism. Based on this hypothesis, the whole genome association of autistic patients in Chinese population was studied. We collected two sample groups, one group of core families (Triads) composed of patients and parents, the other a case control (Case-Control) sample group consisting of sporadic cases and normal controls. We conducted a complete genome association study on two groups of samples and made META analysis, and the results of META analysis were in three European and American populations. META analysis was carried out in the 5 sample groups. The results of the META analysis obtained by the five sample groups were expressed in the brain gene expression data of normal people and autistic patients.
Our results showed that all genomic association studies in two samples of the Chinese population were not found to be significantly related to the whole genome. A combination analysis of the results of the two sample groups found that there were more than one SNPs close to the total genome level in the linkage disequilibrium interval of the chromosome 1p13.2 loci of about 400KB. Two The META analysis of Chinese population samples and 3 American and European population samples showed that 3 SNPs in the 1p13.2 range reached the whole genome significant level (rs936938:p=4.49 x 10-8; rs6537835:p=3.26 * 10-8; rs1877455:p=8.70 x 10-8). The haplotype analysis of the interval found that the 3 whole genome significantly related SNPs were located in 3 and isolated respectively. One type of monomey (AMPD1-NRAS-CSDE1:rs926938|rs8453|rs10489525; TRI M33:rs6537825|rs11582563|rs11585926|rs11589568|rs7511633|rs6661053|rs11102800|rs3827735|rs11102807; TRIM33-BCAS2:rs10858047|rs11587400|rs1877455) exists in the whole genome. The quantitative trait loci analysis shows that the whole genome is significant Multiple SNPs in 3 haplotypes affected CSDE1, NRAS and TRIM33 expression in the human brain prefrontal cortex. Gene differential expression analysis also found TRIM33, NRAS, BCAS2, and CSDE1, and there was a difference in the expression of NRAS, BCAS2, and CSDE1 in autism and normal human brain prefrontal cortex and / or temporal cortex.
Our study found that 3 haplotypes of chromosomal 1p13.2 loci and their associated variants are associated with the risk of autism. Expression of quantitative trait loci and gene differential expression suggests that CSDE1, NRAS and TRIM33 may be a susceptible gene for autism. The interaction of mutations or environmental factors may be one of the causes of autism.
【学位授予单位】：中南大学
【学位级别】：博士
【学位授予年份】：2013
【分类号】：R749.94

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