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1、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 FOURGWAS-hypertension Hypertension is a common disorder and the leading risk factor for cardiovascular disease and premature de

2、aths (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 vari

3、ants (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 ONEGWAS-hypertensionPART ONE 背景知识GWAS(Genome-wide association stu

4、dy)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)4PART ONE 背景知识Genome-wide associa

5、tion 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。5PART 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

6、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？6PART 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

7、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 TWOGWAS-hypertensionPART TWO 研究目的9To evaluate whether the previous reported lo

8、ci 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 variantswould contribute to the traditional cardiovascular risk factors including lipid levels, plas

9、ma 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

10、Chinese Han ancestry. 10方法设计PART THREEGWAS-hypertensionPART THREE 方法设计The discovery stageA meta-analysis consisted of 11816 Han Chinese in six GWASs. In total, 39 SNPs were selected and genotyped for replication 1. 12Replication 1Replication 222 SNPs showing nominal significant association (P 0.05)

11、with SBP, DBP, and/or hypertension in the replication 1 were further genotyped in an independent sample of 22 896 individuals。Replication 3The meta-analysis and replication 1 & 2 found4 novel regions and 4 potential Chinese-specific variants.To minimize the chance of false discovery, we carried thes

12、e 8 novel or Chinese-specific variants forward to replication 3 study comprising 34 142 individuals.PART THREE 方法设计Subsequent Studies13To 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 rep

13、lication samples.Pleiotropic effects of blood pressure loci on established cardiovascular risk factorsCumulative impact of risk alleles on blood pressure and hypertensionWeighted risk scores incorporating the blood pressure variants were calculated to examine the aggregate effect of risk alleles(风险等

14、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)eQ

15、TLs analysis统计分析PART FOURGWAS-hypertensionPART FOUR 统计分析15Meta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：研究间同质性较差研究结果PART FIVEGWAS-hypertensionPART FOUR 研究结果 The discovery and replication study Associations at loci previously identified by GWASNew b

16、lood pressure loci and Chinese-specific variantsPleiotropic effects of blood pressure loci on establishedcardiovascular risk factorsFunctional potential of blood pressure loci by expression quantitative trait loci analysisPathway analysis1234561718Newly identified lociCACNA1DCYP21A2MED13LHLA-BChines

17、e-specific variantsSLC4A7GUCY1A3FLJ32810FURINAssociations at loci previously identified by GWASgenome-wide significanceCASZ1MOV10FGF5CYP17A1SOX6ATP2B1ALDH2JAG1suggestive significanceULK4GUCY1A3HFETBX3less significant levelFIGNTBX3-TBX5PART FOUR 研究结果 Blood pressure and hypertension susceptibility loc

18、i(易感位点) identified by GWAS in the Chinesers820430 near SLC4A7 A Chinese-specific variant in previous reported regions in European populations The reported lead SNP rs13082711 at SLC4A7 in Europeans and rs820430 identified in this study are not in LD.19PART FOUR 研究结果 Regional association plots of blood pressure and hypertension locirs820430SLC4A7PART FOUR 研究结果Cumulative effects of risk alleles on blood pressure levels.20Weighted risk scores were calculated