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Genome-wideassociationstudyinChineseidentifiesnovellociforbloodpressureandhypertension目录背景知识PARTONE目的&对象PARTTWO研究设计PARTTHREE研究结果PARTFIVE研究意义PARTSIX统计分析PARTFOURGWAS-hypertension•Hypertensionisacommondisorderandtheleadingriskfactorforcardiovasculardiseaseandprematuredeaths(早死)worldwide.•Genome-wideassociationstudies(GWASs)intheEuropeanpopulationhaveidentifiedmultiplechromosomalregionsassociatedwithbloodpressure,andtheidentifiedloci(基因位点)altogetherexplainonlyasmallfractionofthevarianceforbloodpressure.•Toidentifynovelgeneticvariants(基因多态性)affectingbloodpressurevariation,thewriterconductedameta-analysisofGWASsofbloodpressureandhypertensionin11816subjectsfollowedbyreplicationstudies(重复试验)including69146additionalindividuals.2背景知识PARTONEGWAS-hypertensionPARTONE背景知识GWAS(Genome-wideassociationstudy)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(singlenucleotidepolymorphism)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。eQTLsanalysis(expressionquantitativetraitlocusanalysis)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)4PARTONE背景知识Genome-wideassociationstudy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。5PARTONE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？6PARTONE背景知识expressionquantitativetraitlocus表达数量性状定位分析•数量性状(QT，QuantitativeTrait)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，QuantitativeTraitLocus)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，expressionquantitativetraitlocusanalysis)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PARTTWOGWAS-hypertensionPARTTWO研究目的9ToevaluatewhetherthepreviousreportedlociassociatedwithbloodpressurecouldbegeneralizedtotheChinesepopulation.ToidentifynewsusceptibilitylociforbloodpressureinChinesepopulation.Toinvestigatewhetherthebloodpressurevariantswouldcontributetothetraditionalcardiovascularriskfactorsincludinglipidlevels,plasmaglucose,andBMI.PARTTWO研究对象ThewriterconductedalargescaleGWASofbloodpressureandhypertensionthatincludedameta-analysisofGWASfrom11816samplesatthediscoverystageandadditional69146samplesinthreeindependentreplicationstudies,involvingatotalof80962subjectsfromChineseHanancestry.10方法设计PARTTHREEGWAS-hypertensionPARTTHREE方法设计ThediscoverystageAmeta-analysisconsistedof11816HanChineseinsixGWASs.Intotal,39SNPswereselectedandgenotypedforreplication1.Thewriterselected15newSNPsthatwereassociatedwithBP(P＜1.0×10−5)and24SNPslocatedinpreviouslyreportedlociatP＜5.0×10−3inthediscoveryanalysisandgenotypedthemin12108Chineseindividuals.12Replication1Replication222SNPsshowingnominalsignificantassociation(P＜0.05)withSBP,DBP,and/orhypertensioninthereplication1werefurthergenotypedinanindependentsampleof22896individuals。Replication3Themeta-analysisandreplication1&2found4novelregionsand4potentialChinese-specificvariants.Tominimizethechanceoffalsediscovery,wecarriedthese8novelorChinese-specificvariantsforwardtoreplication3studycomprising34142individuals.PARTTHREE方法设计SubsequentStudies13•Togainfurtherunderstandingofthebloodpressuresusceptibilityloci(易感基因位点),theirassociationswithlipidlevels,plasmaglucose,andBMIweretestedinthereplicationsamples.PleiotropiceffectsofbloodpressurelocionestablishedcardiovascularriskfactorsCumulativeimpactofriskallelesonbloodpressureandhypertension•Weightedriskscoresincorporatingthebloodpressurevariantswerecalculatedtoexaminetheaggregateeffectofriskalleles(风险等位基因)onbloodpressurelevelsandriskofhypertension.•Toclarifythepossibletranscriptionalmechanisms(转录机制)underlyingtheidentifiedlociinassociationswithBPandHTP,therelationshipsofleadSNPsandproxieswereinvestigatedwithexpressionquantitativetraitlocianalysis.(表达数量性状定位分析)eQTLsanalysis统计分析PARTFOURGWAS-hypertensionPARTFOUR统计分析15•Afixed-effectsmeta-analysis(固定效应meta分析)wasusedtocombinethe6studiesindiscoverystageandtoobtainresultsforeachSNP.(p0.11,𝐼241%)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：p0.1𝐼2检验法：𝐼240%研究结果PARTFIVEGWAS-hypertensionPARTFOUR研究结果ThediscoveryandreplicationstudyAssociationsatlocipreviouslyidentifiedbyGWASNewbloodpressurelociandChinese-specificvariantsPleiotropiceffectsofbloodpressurelocionestablishedcardiovascularriskfactorsFunctionalpotentialofbloodpressurelocibyexpressionquantitativetraitlocianalysisPathwayanalysis1234561718NewlyidentifiedlociCACNA1DCYP21A2MED13LHLA-BChinese-specificvariantsSLC4A7GUCY1A3FLJ32810FURINAssociationsatlocipreviouslyidentifiedbyGWASgenome-widesignificanceCASZ1MOV10FGF5CYP17A1SOX6ATP2B1ALDH2JAG1suggestivesignificanceULK4GUCY1A3HFETBX3lesssignificantlevelFIGNTBX3-TBX5PARTFOUR研究结果Genome-widesignificance：P＜5.0×10−8Suggestivesignificance：P＜5.0×10−5Lesssignificantlevel：P＜5.0×10−3Bloodpres