本文選題：散發(fā)性肌萎縮側(cè)索硬化癥 + 神經(jīng)系統(tǒng)發(fā)育通路�。� 參考：《南昌大學(xué)》2017年碩士論文

【摘要】：目的:肌萎縮側(cè)索硬化癥(amyotrophic lateral sclerosis,ALS)是一種罕見的和毀滅性的神經(jīng)退行性疾病,主要累及運(yùn)動(dòng)神經(jīng)元導(dǎo)致進(jìn)行性麻痹,并最終致死。ALS約5%~10%的患者有家族史,稱為家族性肌萎縮側(cè)索硬化癥(FALS),剩余90%~95%屬于散發(fā)性肌萎縮側(cè)索硬化癥(sALS)。散發(fā)性肌萎縮側(cè)索硬化癥是一種受遺傳和環(huán)境共同影響的衰老性復(fù)雜疾病。目前,全基因組關(guān)聯(lián)研究(Genome-wide association study,GWAS)已經(jīng)揭示了很多易感基因和大量的風(fēng)險(xiǎn)SNP位點(diǎn)與sALS有關(guān),但是其致病的分子機(jī)制仍需進(jìn)一步探索。更重要的是,現(xiàn)有的GWAS篩查之間的重復(fù)性低;且?guī)缀跛械暮Y查僅針對(duì)嚴(yán)格符合全基因組顯著性水平(P10-5)的少數(shù)位點(diǎn)開展研究,大量微小效應(yīng)的遺傳變異被忽略。據(jù)此本研究通過整合多個(gè)GWAS篩查與sALS相關(guān)的微小效應(yīng)位點(diǎn);利用通路分析探討可能致ALS的分子機(jī)制;進(jìn)一步通過兩階段的關(guān)聯(lián)分析策略發(fā)現(xiàn)并驗(yàn)證中國(guó)人群特異的功能基因。方法:基于兩個(gè)不同族群來源的sALS相關(guān)的全基因組關(guān)聯(lián)研究(GWAS)(美國(guó)和愛爾蘭研究)構(gòu)建sALS相關(guān)整合數(shù)據(jù)集。通過基因集富集分析(Gene set enrichment analysis,GSEA),評(píng)價(jià)族群間GWAS的重復(fù)性。利用通路分析揭示兩研究間共支持的功能通路,以及在這些通路中sALS相關(guān)的易感基因。為了進(jìn)一步驗(yàn)證sALS與功能相關(guān)靶基因之間的關(guān)聯(lián),我們采用了兩階段病例對(duì)照研究(500例sALS患者,500例健康對(duì)照)。發(fā)現(xiàn)并分步驟驗(yàn)證候選基因的sALS易感位點(diǎn)。結(jié)果:通過對(duì)兩個(gè)sALS相關(guān)的全基因組關(guān)聯(lián)研究(GWAS)(美國(guó)和愛爾蘭研究)的整合分析,本研究在3,227個(gè)亞顯著候選基因集中發(fā)現(xiàn)了371個(gè)共支持易感基因;而GSEA分析,不僅表明兩研究在整體水平(P10-4)存在顯著重復(fù)性,也提示兩個(gè)GWAS篩查所確定的ALS易感基因具有相似的功能背景。通路分析發(fā)現(xiàn)這兩個(gè)獨(dú)立研究間存在34個(gè)共支持的GO(Gene Ontology)生物過程(biological processes)通路(P10-2),其中10個(gè)通路與NSD功能有關(guān)。而基于79個(gè)已報(bào)道的ALS易感或致病基因的通路分析,也印證了NSD在ALS發(fā)病進(jìn)程中的重要作用(P=0.0013)。在這些通路中,與神經(jīng)系統(tǒng)發(fā)育功能(nervous system development,NSD-function)有關(guān)的神經(jīng)系統(tǒng)發(fā)育通路(nervous system developmental pathway,GO:0007399)進(jìn)一步被已報(bào)道的sALS的易感及致病基因所支持。在基于中國(guó)人群的全基因組病例對(duì)照研究中,17個(gè)NSD功能相關(guān)的共支持易感基因中,有4個(gè)(DISC1,CNTN4,NRXN3和ERBB4)呈現(xiàn)出與sALS有顯著關(guān)聯(lián)(P0.01)。而在第二階段中國(guó)漢族人群病例對(duì)照研究的進(jìn)一步印證中,參與神經(jīng)系統(tǒng)發(fā)育通路的DISC1基因的多態(tài)性位點(diǎn)rs3737597與sALS密切相關(guān)。結(jié)論:神經(jīng)系統(tǒng)發(fā)育通路是sALS的一種潛在發(fā)病機(jī)制,其中DISC1基因的rs3737597基因型多態(tài)性可能發(fā)揮了一些作用;用結(jié)合了低顯著性閾值和通路分析的整合策略來闡明復(fù)雜疾病的發(fā)病機(jī)制是可行的。
[Abstract]:Objective: amyotrophic lateral sclerosis (amyotrophic lateral sclerosis) is a rare and destructive neurodegenerative disease, involving motor neurons leading to progressive paralysis, and resulting in death. About 50.0% of the patients have a family history. It is called familial amyotrophic lateral sclerosis, the remaining 90% belongs to sporadic amyotrophic lateral sclerosis. Sporadic amyotrophic lateral sclerosis is a complex aging disease affected by heredity and environment. At present, Genome-wide association study has revealed that many susceptible genes and a large number of risk SNP loci are associated with sALS, but the molecular mechanism of its pathogenicity needs to be further explored. More importantly, there is low reproducibility among the existing GWAS screening, and almost all of the screening studies are carried out on a few sites that are strictly consistent with the whole genome significance level (P10-5), and a large number of genetic variations with small effects are ignored. In this study, we integrated multiple GWAS screening microeffector sites associated with sALS, explored the molecular mechanisms that might cause ALS by pathway analysis, and further identified and validated specific functional genes in Chinese population by two-stage association analysis strategy. Methods: sALS related integrated data sets were constructed based on sALS associated genome-wide association study of two different ethnic groups (American and Irish studies). Gene set enrichment analysis was used to evaluate the reproducibility of GWAS among different populations. Pathway analysis was used to reveal the co-supporting functional pathways and the susceptibility genes associated with sALS in these pathways. To further verify the association between sALS and function-related target genes, a two-stage case-control study was conducted in 500 patients with sALS and 500 healthy controls. SALS susceptibility sites of candidate genes were identified and verified step by step. Results: based on the integrative analysis of two genome-wide association studies related to sALS, GWASA (American and Irish study), 371 co-supporting susceptible genes were found in 321 subsignificant candidate genes, while GSEA analysis, Not only does the two studies have significant reproducibility at the whole level of P10-4] but also the ALS susceptibility genes identified by the two GWAS screening have similar functional background. Pathway analysis revealed that there were 34 GO(Gene Ontology biological processes (P10-2) pathways between the two independent studies, 10 of which were related to the function of NSD. Based on the pathway analysis of 79 reported genes of ALS susceptibility or pathogenicity, it is confirmed that NSD plays an important role in the pathogenesis of ALS. Among these pathways, the neurodevelopmental pathway associated with nervous system development (NSD-function) is further supported by the reported susceptibility and pathogenicity of sALS. In a genome-wide case-control study based on Chinese population, four of the 17 co-supporting susceptibility genes associated with NSD function showed significant association with sALS. In the second stage of the case control study in Chinese Han population, the polymorphic rs3737597 of the DISC1 gene involved in the neurodevelopmental pathway was closely related to sALS. Conclusion: the neurodevelopmental pathway is a potential pathogenesis of sALS, in which the rs3737597 genotype polymorphism of DISC1 gene may play a role in the pathogenesis of sALS. It is feasible to elucidate the pathogenesis of complex diseases by integrating low significant threshold and pathway analysis.
【學(xué)位授予單位】：南昌大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R744.8

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