1、Genome-wide association study in Chinese identifies novel loci for blood pressure and hypertension目錄背景知識PART ONE目的&對象PART TWO研究設計PART THREE研究結果PART FIVE研究意義PART SIX統(tǒng)計分析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(基因位點)altogether explain only a small fraction of the variance for blood pressure. To identify novel genetic vari

3、ants (基因多態(tài)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(重復試驗) including 69146 additional individuals.2背景知識PART ONEGWAS-hypertensionPART ONE 背景知識GWAS(Genome-wide association stu

4、dy)全基因組關聯(lián)分析，是指在人類全基因組范圍內(nèi)找出存在的序列變異，即單核苷酸多態(tài)性（SNP），從中篩選出與疾病相關的SNPs。SNPs(single nucleotide polymorphism)單核苷酸多態(tài)性，是指基因組中核苷酸的變異而引起的DNA序列多樣性，包括點突變、單個堿基的插入、缺失和置換。eQTLs analysis (expression quantitative trait locus analysis)表達數(shù)量性狀定位分析，將基因的表達水平作為數(shù)量性狀，采用QTL分析定位控制該基因表達的QTL(eQTLs)4PART ONE 背景知識Genome-wide associa

5、tion study全基因組關聯(lián)分析最早于1996 年提出，將人類復雜疾病的研究從候選基因轉向全基因組水平，在群體水平檢測全基因組范圍的遺傳變異與可觀測性狀間的遺傳關聯(lián)，用更大規(guī)模的檢測得到與疾病相關的每一個基因。5PART ONE 背景知識Polymorphism基因多態(tài)性多態(tài)性是指處于隨機婚配的群體中，同一基因位點可存在兩種以上的基因型。如果某位點上所有的等位基因頻率均大于0.01，攜帶該等位基因的雜合子頻率大于2%，則認為該基因座具有多態(tài)性。 1.限制性片段長度多態(tài)性RFLP 限制性酶切位點多態(tài)性切割基因組時產(chǎn)生的片段數(shù)目及長度不一； 2.可變數(shù)目串聯(lián)重復序列VNTRS 一些短的核苷酸序

6、列重復次數(shù)不同所致；小衛(wèi)星DNA&微衛(wèi)星DNA遺傳標志； 3.單核苷酸多態(tài)性SNP 基因組中核苷酸的變異引起的DNA序列多樣性，包括點突變、單個堿基插入、缺失、置換。 注：染色體、基因、block和SNP這四者大致是什么關系？6PART ONE 背景知識expression quantitative trait locus表達數(shù)量性狀定位分析 數(shù)量性狀(QT，Quantitative Trait) 生物體的一些性狀是由多基因共同控制的，其測量值可以用連續(xù)的數(shù)量進行表示，這些性狀統(tǒng)稱為 數(shù)量性狀。數(shù)量性狀定位分析(QTL 分析，Quantitative Trait Locus) 它指的是定位控制

7、數(shù)量性狀的基因在基因組中的位置，實際上是借助一些分子標記分析數(shù)量性狀的 關系，將數(shù)量性狀對應的QTL定位于分子標記間。 表達數(shù)量性狀定位分析(eQTLs分析，expression quantitative trait locus analysis) 將基因的表達水平作為數(shù)量性狀，采用QTL分析定位控制該基因表達的QTL(eQTLs)，一個eQTL是 染色體上的一個位點，可包含若干個基因，這些基因控制某個基因的遺傳表達。7目的&對象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 研究對象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方法設計PART THREEGWAS-hypertensionPART THREE 方法設計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 方法設計Subsequent Studies13To gain further understanding of the blood pressure susceptibility loci(易感基因位點), 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(風險等

14、位基因) on blood pressure levels and risk of hypertension.To clarify the possible transcriptional mechanisms(轉錄機制) 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.(表達數(shù)量性狀定位分析)eQ

15、TLs analysis統(tǒng)計分析PART FOURGWAS-hypertensionPART FOUR 統(tǒng)計分析15Meta分析效應模型固定效應模型假設所有納入研究有一個真實效應研究結果件差異視為抽樣誤差影響適用于：研究間同質性較好隨機效應模型假設所有納入研究有多個真實效應允許不同研究結果間真實效應不同適用于：研究間同質性較差研究結果PART FIVEGWAS-hypertensionPART FOUR 研究結果 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 研究結果 Blood pressure and hypertension susceptibility loc

18、i(易感位點) 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 研究結果 Regional association plots of blood pressure and hypertension locirs820430SLC4A7PART FOUR 研究結果Cumulative effects of risk alleles on blood pressure levels.20Weighted risk scores were calculated