基于全基因组双变量分析探索2型糖尿病与早期体重指标新的变异

发布时间：2018-01-02 15:40

本文关键词：基于全基因组双变量分析探索2型糖尿病与早期体重指标新的变异　出处：《南方医科大学》2017年博士论文　论文类型：学位论文

【摘要】：[背景及目的]糖尿病是一组以高血糖为特征的代谢性疾病。2型糖尿病(type 2 diabetes,T2D)是糖尿病最常见类型,超过90%。目前在全球有超过4亿糖尿病患者,已成为致死、致残和高额医疗费用的主要原因之一。有研究表明早期体重指标包括出生体重(birth weight,BW)及儿童体重指数(childhood body mass index,CBMI)与T2D的发生明显相关。低的BW和高CBMI均会增加T2D的发生风险。全基因组关联研究(genome-wide association study,GWAS)也证实了它们之间一些共同的单核苷酸多态(single nucleotide polymorphisms,SNP),但这些SNP只能解释三者极少量的遗传信息。最近有研究利用多效性已知条件错误发现率(pleiotropy-informed conditional false discovery rate,PCFDR)法成倍地增加了一些疾病及表型新的及共有的SNP的发现率。本研究为了进一步明确T2D与BW/CBMI共有的遗传机制,利用PCFDR法探索T2D与BW/CBMI共效的变异,为探索新的及共同的干预靶点提供依据。[方法]采用了 PCFDR法整合目前全球T2D与BW/CBMI最大的GWAS汇总数据进行双变量分析,以条件错误发现率(conditional false discovery rate,cFDR)0.05为统计阈值。[结果]1本研究QQ图结果发现以T2D与BW/CBMI均具有较强的富集趋势。2鉴定出的新的及共效的变异2.1以BW及CBMI为条件,分别鉴定出133个及139个与T2D相关的SNP,其中120个和125个是新发现的。2.2以T2D为条件,分别鉴定出13个及37个与BW和CBMI相关的SNP,其中12个和25个是新发现的。2.3发现了9个T2D与BW共效的SNP(7个新的),10个T2D与CBMI新的共效的SNP。2.4证实了CDKAL1和ADCY5基因与低BW及T2D有显著相关,其可能通过胚胎胰岛素假说导致两者发生。2.5证实了GNPDA 基因与高CBMI及T2D有显著相关,其可能通过中枢神经系统对体重的调控导致两者发生。3鉴定出的SNP相对应的基因功能分析3.1基因网络分析结果显示以BW为条件鉴定出相应T2D的靶基因蛋白在的蛋白质-蛋白质相互作用的网络中显示了较强的关联作用,该网络包括细胞过程基因的正调控和RNA聚合酶Ⅱ启动子基因的转录负调控;以CBMI为条件鉴定出相应T2D的靶基因蛋白也显示了类似强度的关联作用,网络包括多细胞生物的发展、解剖结构的形成和细胞成分的正调控等。3.2对BW及T2D的共效基因进行生物医学通路分析结果显示腺苷受体信号通路、G蛋白偶联嘌呤能受体信号转导通路及腺苷酸环化酶激活多巴胺受体信号通路为最显著相关的三条生物医学信号通路(P均0.01)。[结论]1证实了PCFDR方法在GWAS中鉴定新的基因或变异的强大功效。2鉴定出T2D与BW/CBMI新的及共同的基因或变异,为T2D发病机制的解释增添了新的内容。3为进一步的生物学实验与临床验证提供了理论依据及新的思路。
[Abstract]:[background and objective: diabetes is a high glucose metabolic disease characterized by type.2 diabetes (type 2 diabetes, T2D) is the most common type of diabetes, more than 90%. in the world currently has more than 400 million patients with diabetes, has become one of the main causes of death, disability and high medical costs. Studies have shown that early weight the index including birth weight (birth weight, BW) and body mass index (childhood body mass's index, CBMI) was significantly associated with the occurrence of T2D. Low BW and high CBMI may increase the risk of T2D. A genome-wide association study (genome-wide association study, GWAS) also confirmed some common single nucleotide polymorphism between them (single nucleotide polymorphisms, SNP SNP), but these can only explain the genetic information of very small amounts of three. Recent studies have pleiotropic effects using known conditions the false discovery rate (pleiotropy-informed conditi Onal false discovery rate, PCFDR) were multiplied some diseases and new phenotype and shared the detection rate of SNP. The purpose of this study is to further clarify the T2D and BW/CBMI common genetic mechanisms, explore the variation of T2D and BW/CBMI were effective by PCFDR method, to provide the basis. Methods using PCFDR method to integrate the current global T2D the largest GWAS and BW/CBMI data were pooled for bivariate analysis to explore new and common intervention targets, in conditions of false discovery rate (conditional false discovery rate, cFDR) 0.05 as the statistical threshold. This research results of]1 QQ found in T2D and BW/CBMI had strong enrichment trend identified by the new.2 the total efficiency and 2.1 of the variance in BW and CBMI, were identified in 133 and 139 associated with T2D SNP, of which 120 and 125 are newly discovered.2.2 in T2D, were identified in 13 and 37 with BW and CBM I SNP, of which 12 and 25 are newly discovered.2.3 found 9 T2D and BW were effective SNP (7 new), 10 T2D CBMI and the new total efficiency was confirmed by SNP.2.4, CDKAL1 and ADCY5 genes were significantly associated with low BW and T2D, which may be through the embryo both insulin hypothesis leads to occurrence of.2.5 have confirmed the GNPDA gene was significantly associated with high CBMI and T2D, the central nervous system regulation of body weight caused by gene function between the two.3 identified SNP corresponding to the analysis of 3.1 gene network analysis results showed that BW showed strong association conditions identified target genes the corresponding protein T2D in the protein-protein interaction network, the network includes the positive regulation of cell gene and RNA polymerase II transcription negative regulator gene; CBMI conditions identified target gene protein T2D also shows the class Like interaction strength, network including the development of multicellular organisms, anatomical formation and cell component structure of the positive regulation of.3.2 on BW and T2D genes were biological pathway analysis showed that adenosine receptor signaling pathway, G protein coupled purinergic receptor signal transduction pathway and adenylate cyclase activation of dopamine receptor signaling pathway as the three most significant related biomedical signal pathway (P 0.01). Conclusion]1 confirmed the identification of PCFDR gene or new mutation in GWAS powerful.2 identified T2D and BW/CBMI new and common genes or mutation, T2D pathogenesis explanation adds new contents for.3 the theoretical basis and new ideas for further biological experiments and clinical verification.

【学位授予单位】：南方医科大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R587.1

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