本文選題：孤獨(dú)癥 + 全基因組關(guān)聯(lián)研究�。� 參考：《中南大學(xué)》2013年博士論文

【摘要】：兒童孤獨(dú)癥是一種嚴(yán)重影響兒童健康,并且具有高度臨床和遺傳異質(zhì)性的神經(jīng)發(fā)育障礙性疾病。孤獨(dú)癥患病率近年急劇上升,美國政府公布的最新數(shù)據(jù)顯示,每50個(gè)兒童中就有一個(gè)患有孤獨(dú)癥。按照目前全球普遍的發(fā)病率估算,我國的孤獨(dú)癥患者已達(dá)一千多萬。已有病因?qū)W研究發(fā)現(xiàn),遺傳和環(huán)境因素均參與孤獨(dú)癥的發(fā)生,且遺傳因素在孤獨(dú)癥的病因中占主要作用,其遺傳度高達(dá)90%。罕見或新發(fā)變異,如染色體異常,新發(fā)和罕見的拷貝數(shù)變異以及新發(fā)和罕見的單核苷酸變異和小的插入／缺失變異均被發(fā)現(xiàn)參與孤獨(dú)癥的遺傳病因。通過罕見變異研究已經(jīng)發(fā)現(xiàn)了多個(gè)孤獨(dú)癥相關(guān)的位點(diǎn)／區(qū)間和易感或致病基因。盡管如此,這些新發(fā)或罕見的孤獨(dú)癥遺傳病因只能解釋一小部分病人,絕大多數(shù)孤獨(dú)癥的遺傳病因仍然未知。 孤獨(dú)癥是一個(gè)涉及環(huán)境和遺傳病因的復(fù)雜疾病,多個(gè)常見變異或常見變異與環(huán)境風(fēng)險(xiǎn)因素共同或交互作用被認(rèn)為在孤獨(dú)癥病因中起到重要作用。與孤獨(dú)癥的新發(fā)和罕見遺傳變異研究相比,通過全基因組關(guān)聯(lián)研究發(fā)現(xiàn)的常見變異還比較少,目前只發(fā)現(xiàn)CDH9-CDH10, SEMA5A以及MACROD2幾個(gè)基因或位點(diǎn)。我們認(rèn)為多個(gè)常見變異共同或通過與環(huán)境相互作用會(huì)導(dǎo)致孤獨(dú)癥的發(fā)生,是孤獨(dú)癥可能的病因之一�；谶@一假設(shè),本研究進(jìn)行了中國人群孤獨(dú)癥患者的全基因組關(guān)聯(lián)研究。我們收集了兩個(gè)樣本組,一組為由患者和父母親組成的核心家系(Triads)樣本組,另一組為由散發(fā)病例和正常對(duì)照組成的病例-對(duì)照(Case-Control)樣本組。我們對(duì)兩組樣本分別進(jìn)行全基因組關(guān)聯(lián)研究并做META分析,META分析的結(jié)果在三個(gè)歐美人群中進(jìn)行驗(yàn)證,并對(duì)5個(gè)樣本組進(jìn)行META分析。五個(gè)樣本組META分析得到的全基因組顯著關(guān)聯(lián)的結(jié)果在正常人和孤獨(dú)癥患者的腦基因表達(dá)數(shù)據(jù)中進(jìn)行表達(dá)定量形狀位點(diǎn)分析和基因差異表達(dá)分析。 我們的研究結(jié)果顯示中國人群兩個(gè)樣本組的全基因組關(guān)聯(lián)研究結(jié)果均未發(fā)現(xiàn)全基因組顯著相關(guān)位點(diǎn)。對(duì)兩個(gè)樣本組的結(jié)果進(jìn)行結(jié)合分析發(fā)現(xiàn)在染色體1p13.2位點(diǎn)約400kb的連鎖不平衡區(qū)間內(nèi)有多個(gè)SNPs接近全基因組顯著性相關(guān)水平。兩個(gè)中國人群樣本與3個(gè)歐美人群樣本的META分析顯示,1p13.2區(qū)間內(nèi)的3個(gè)SNPs達(dá)到了全基因組顯著性水平(rs936938:p=4.49×10-8; rs6537835:p=3.26×10-8; rs1877455:p=8.70×10-8)。對(duì)該區(qū)間的單體型分析發(fā)現(xiàn),該3個(gè)全基因組顯著性相關(guān)的SNPs分別位于3個(gè)與孤獨(dú)癥存在全基因組顯著關(guān)聯(lián)的單體型(AMPD1-NRAS-CSDE1:rs926938|rs8453|rs10489525; TRI M33:rs6537825|rs11582563|rs11585926|rs11589568|rs7511633|rs6661053|rs11102800|rs3827735|rs11102807;TRIM33-BCAS2:rs10858047|rs11587400|rs1877455)。表達(dá)定量性狀位點(diǎn)分析發(fā)現(xiàn)全基因組顯著相關(guān)的3個(gè)單體型內(nèi)的多個(gè)SNPs影響到了CSDE1, NRAS以及TRIM33在人腦前額皮層中mRNA的表達(dá)水平,基因差異表達(dá)分析也發(fā)現(xiàn)TRIM33, NRAS, BCAS2以及CSDE1和在孤獨(dú)癥和正常人腦前額皮層和／或顳葉皮層中存在表達(dá)差異。 我們的研究發(fā)現(xiàn)染色體1p13.2位點(diǎn)的3個(gè)單體型及其相關(guān)變異與孤獨(dú)癥的發(fā)病風(fēng)險(xiǎn)相關(guān)。表達(dá)定量性狀位點(diǎn)和基因差異表達(dá)分析提示CSDE1, NRAS和TRIM33可能是孤獨(dú)癥的易感基因。本研究提示常見變異在孤獨(dú)癥發(fā)生中起到一定作用,多個(gè)常見變異共同或與環(huán)境因素相互作用可能是孤獨(dú)癥發(fā)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.
【學(xué)位授予單位】：中南大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2013
【分類號(hào)】：R749.94

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相關(guān)期刊論文 前1條

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