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Genome-wide association,study,in Chinese identifies novel,loci,for,blood pressure and hypertension,目录,背景,知识,PART,ONE,目的,&,对象,PART,TWO,研究设计,PART,THREE,研究结果,PART,FIVE,研究意义,PART,SIX,统计分析,PART,FOUR,GWAS-hypertension,Hypertension,is,a common disorder,and the leading risk factor for,cardiovascular disease and premature deaths,(,早死,)worldwide,.,Genome-wide association studies(GWASs),in the European population have identified multiple chromosomal regions associated with blood pressure,and the identified,loci(,基因位点,)altogether,explain,only a small fraction,of the variance for blood pressure.,To,identify novel genetic variants,(,基因多态性,)affecting,blood pressure variation,the writer,conducted a,meta-analysis,of GWASs,of blood pressure and hypertension in,11816,subjects followed by,replication,studies,(,重复试验,),including 69146,additional individuals.,2,背景知识,PART,ONE,GWAS-hypertension,PART,ONE,背景知识,GWAS(Genome-wide,association,study,),全,基因组关联分析,，是指在人类全基因组范围内找出存在的序列变异，即单核苷酸多态性（,SNP,），从中筛选出与疾病相关的,SNPs,。,SNPs(single nucleotide polymorphism),单核苷酸,多态性,，是指基因组中核苷酸的变异而引起的,DNA,序列多样性，包括点突变、单个碱基的插入、缺失和置换。,eQTLs analysis(expression,quantitative trait,locus,analysis,),表达数量性状定位,分析,，,将,基因的表达水平作为数量性状，采用,QTL,分析定位控制该基因表达的,QTL(eQTLs),4,PART,ONE,背景,知识,Genome-wide,association,study,全基因组关联分析,最早于,1996,年提出，将人类复杂疾病的研究,从,候选基因,转向,全基因组水平,，,在,群体水平,检测,全基因组范围,的遗传变异与可观测性状间的遗传,关联，用,更大规模的检测得到与疾病相关的每一个基因,。,5,PART,ONE,背景知识,Polymorphism,基因多态性,多态性是指处于随机婚配的群体中，同一基因位点可存在两种以上的基因型。如果某位点上所有的,等位基因频率均大于,0.01,，携带该等位基因的杂合子频率大于,2%,，则认为该基因座具有多态性。,1.,限制性片段长度多态性,RFLP,限制性酶切位点多态性切割基因组时产生的片段数目及长度不一；,2.,可变数目串联重复序列,VNTRS,一些短的核苷酸序列重复次数不同所致；小卫星,DNA&,微卫星,DNA,遗传标志,；,3.,单核苷酸多态性,SNP,基因组中,核苷酸的变异,引起的,DNA,序列多样性,，包括点突变、单个碱基插入、缺失、置换,。,注,：染色体、基因、,block,和,SNP,这四者大致是什么关系？,6,PART,ONE,背景知识,expression quantitative trait locus,表达,数量性状定位分析,数量性状,(QT,，,Quantitative Trait),生物体,的一些性状是由多基因共同控制的，其测量值可以用,连续的数量,进行表示，这些性状,统称为,数量性状。,数量性状定位分析,(QTL,分析，,Quantitative Trait Locus),它,指的是定位,控制数量性状的基因,在基因组中的,位置,，实际上是借助一些分子标记分析数量性状,的,关系,，将数量性状对应的,QTL,定位于分子标记间。,表达数量性状定位分析,(eQTLs,分析，,expression,quantitative trait,locus analysis),将,基因的表达水平,作为数量性状，采用,QTL,分析,定位,控制该基因表达的,QTL,(eQTLs),，一个,eQTL,是,染色体,上的一个位点,，可,包含若干个基因，这些基因控制某个基因的遗传,表达。,7,目的,&,对象,PART,TWO,GWAS-hypertension,PART,TWO,研究目的,目的,OBJECTIVE,9,To,evaluate,whether,the,previous,reported,loci,associated with blood pressure could be,generalized,to,the,Chinese population,.,To,identify,new susceptibility loci,for blood,pressure in,Chinese,population.,To,investigate,whether,the,blood pressure variants,would,contribute to,the,traditional cardiovascular risk factors,including,lipid levels,plasma glucose,and BMI.,PART,TWO,研究对象,The writer conducted,a large,scale GWAS,of,blood pressure,and hypertension,that included,a meta-analysis of GWAS,from 11816,samples,at the,discovery stage,and,additional,69146 samples,in three independent,replication studies,involving,a total,of,80962,subjects from Chinese Han ancestry,.,10,对象,SAMPLES,方法,设计,PART,THREE,GWAS-hypertension,PART,THREE,方法设计,The discovery stage,A meta-analysis,consisted,of 11816,Han Chinese,in six,GWASs.In total,39 SNPs,were selected,and genotyped,for replication 1.,The writer selected,15 new SNPs,that were associated with BP,(,P,),and,24 SNPs,located in,previously reported,loci,at,P,in,the discovery,analysis and,genotyped them in,12108,Chinese,individuals.,12,Replication 1,Replication 2,22,SNPs,showing,nominal significant association(P,0.05),with SBP,DBP,and/or hypertension,in the replication 1,were further,genotyped in an independent sample of 22 896 individuals,。,Replication 3,The,meta-analysis,and,replication 1,&2 found,4 novel regions,and,4 potential Chinese-specific,variants,.,To minimize the chance of false discovery,we carried,these 8,novel or,Chinese-specific variants,forward to,replication 3,study comprising 34 142 individuals.,PART,THREE,方法设计,Subsequent Studies,13,To,gain further understanding of the blood pressure,susceptibility loci,(,易感基因位点,),their associations,with,lipid levels,plasma glucose,and BMI,were tested in,the replication samples.,Pleiotropic effects of blood pressure loci on,established cardiovascular,risk factors,Cumulative,impact,of risk alleles on blood pressure and hypertension,Weighted risk scores incorporating the,blood,pressure,variants were,calculated to examine the aggregate effect of risk,alleles(,风险等位基因,)on,blood pressure levels and risk of hypertension.,To,clarify the possible transcriptional,mechanisms(,转录机制,)underlying the,identified loci in associations with,BP,and,HTP,the,relationships of lead SNPs,and,proxies,were,investigated,with expression quantitative trait,loci,analysis.,(,表达数量性状定位分析,),eQTLs analysis,统计分析,PART,FOUR,GWAS-hypertension,PART,FOUR,统计分析,15,A,fixed-effects,meta-analysis,(,固定,效应,meta,分析,),was,used to combine,the 6 studies in discovery stage and to obtain results for each SNP.,(p0.11,),Meta,分析,效应模型,固定效应模型,假设所有纳入研究有一个真实效应,研究结果件差异视为抽样误差影响,适用于：研究间同质性较好,随机效应模型,假设所有纳入研究有多个真实效应,允许不同研究结果间真实效应不同,适用于：研究间同质性较差,Q,检验法：,p0.1,检验法：,40%,研究结果,PART,FIVE,GWAS-hypertension,PART,FOUR,研究结果,The