Genetics of Hypertension Risk Factors and Sequela in African Americans

非裔美国人高血压危险因素和后遗症的遗传学

• 批准号: 7831823
• 负责人: Yan Sun
• 金额: $ 47.63万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7831823
• 关键词: Address; African; African American; Area; Arterial Disorder; Blood Pressure; Cardiovascular Diseases; Cardiovascular system; Characteristics; Cohort Studies; Copy Number Polymorphism; DNA; Data; Development; Disease; Disease susceptibility; Echocardiography; Epidemiology; Ethnic group; European; Frequencies; Gene Dosage; Gene Frequency; Genes; Genetic; Genetic Variation; Genomics; Genotype; Heart Diseases; Human; Human Genome; Hypertension; Individual; Kidney Diseases; Left Ventricular Hypertrophy; Linkage Disequilibrium; Measures; Meta-Analysis; Methods; Modification; National Heart, Lung, and Blood Institute; Obesity; Organ; Performance; Phase; Population; Population Genetics; Population Study; Renal function; Reporting; Research Personnel; Resources; Risk Factors; Sampling; Serinus; Single Nucleotide Polymorphism; Structure; Testing; Validation; Variant; cohort; design; disorder risk; familial hypertension; genetic epidemiology; genetic variant; genome sequencing; genome wide association study; genome-wide; heart disease risk; improved; public health relevance; tool; trait

DESCRIPTION (provided by investigator): This application addresses broad Challenge Area (08) Genomics and specific Challenge Topic, 08-HL-104: Assess genetic variation in African Americans and determine its effect on disease. Genome-wide association studies (GWAS) have successfully identified genomic loci associated with hypertension and its risk factors in recent years. However, previous GWAS were conducted in populations of European ancestry rather than populations of African Ancestry. Resources are lacking for imputation of existing single nucleotide polymorphisms (SNPs) or for the assessment of copy number variations (CNVs) and their relation to disease in individuals of African ancestry. National Heart, Lung and Blood Institute (NHLBI) has recommended an increased focus on the examination of the genetic variants (SNPs and CNVs) and their associations with common disease traits in the cohorts of African Americans. African Americans are an admixed population with both European and African ancestries. The population genetics (eg. linkage disequilibrium and allele frequencies) of African Americans are appreciably different from either of their ancestries. To appropriately design and conduct the GWAS of heart disease in African Americans, the characteristics of the genome-wide markers, such as single nucleotide polymorphism (SNP) and copy number variation (CNV), and the performance of the necessary tools for statistical analyses, such as genotype imputation and CNV calling, have to be assessed and evaluated in African American samples. The Genetic Epidemiology Network of Arteriopathy (GENOA) and HyperGEN were both initiated in 1995 to study the genetics of hypertension and its target-organ complications in sibships in multiple ethnic groups. Both cohorts have measured 906,600 SNPs and 946,000 CNV probes using Affymetrix 6.0 array on their African American subjects. In this application, we propose to estimate the characteristics of population genetics, to evaluate the performance of existing GWAS analysis tools, and to conduct a genome-wide association study of blood pressures and echocardiography traits, utilizing SNPs and CNVs identified on 1,854 African Americans from the GENOA and 1,802 African Americans from the HyperGEN, with the following specific aims: Aim 1. To characterize the distribution of copy number variations (CNVs) in African American populations, we will apply two CNV calling methods, Canary and HelixTree CNAM, using all genome-wide SNP probes and CNV probes on the Affymetrix 6.0 array. The results will be compared using two independent African American populations from the GENOA and HyperGEN studies. Aim 2: To identify genome-wide regions containing evidence of disease susceptibility loci for hypertension, obesity, left ventricular hypertrophy, and kidney function, we will perform analyses in each African American populations to identify associated CNVs and SNPs. To reduce false positives, associations will be adjusted for multiple testing and population substructure, and compared for replication. Pooled analysis will be conducted to increase power to identify associated genetic variants by combining results from GENOA and HyperGEN. Aim 3: To evaluate the performance of existing genotype imputation methods for African Americans, we will compare the performance of different imputation methods (MACH, IMPUTE and BEAGLE) in two African American populations. To improve the imputation accuracy of African American subjects, we will sequence genomic regions with poor imputation accuracy to understand the LD structure and identify the causes of inaccurate imputation. PUBLIC HEALTH RELEVANCE: The genetic variants in the human genome and their associations with cardiovascular diseases and hypertension have been inadequately studied in African American populations. Using the available genotyping data of 906,600 SNPs and 946,000 copy number variation (CNV) probes, and previously collected epidemiological data on 3,658 African Americans (1,854 GENOA and 1,804 HyperGEN), we will investigate the characteristics of population genetics (SNPs and CNVs), and conduct genome-wide association analyses of hypertension risk factors and sequelae. The characteristics of population genetics and the significant CNV effects will be replicated in two independent African American populations from GENOA and HyperGEN.

描述（由研究者提供）：该应用程序涉及广泛的挑战领域 (08) 基因组学和特定挑战主题，08-HL-104：评估非裔美国人的遗传变异并确定其对疾病的影响。近年来，全基因组关联研究（GWAS）已成功鉴定出与高血压及其危险因素相关的基因组位点。然而，之前的 GWAS 是在欧洲血统人群而不是非洲血统人群中进行的。缺乏资源来估算现有的单核苷酸多态性 (SNP) 或评估拷贝数变异 (CNV) 及其与非洲血统个体疾病的关系。美国国家心肺和血液研究所 (NHLBI) 建议更加关注非裔美国人群体中遗传变异（SNP 和 CNV）及其与常见疾病特征的关联的检查。非裔美国人是具有欧洲和非洲血统的混合人群。非裔美国人的群体遗传学（例如连锁不平衡和等位基因频率）与其祖先有明显不同。为了正确设计和开展非裔美国人心脏病的 GWAS，必须在非裔美国人样本中评估和评估全基因组标记的特征，如单核苷酸多态性 (SNP) 和拷贝数变异 (CNV)，以及统计分析所需工具的性能，如基因型插补和 CNV 调用。动脉病遗传流行病学网络 (GENOA) 和 HyperGEN 均于 1995 年启动，旨在研究多个民族同胞中高血压及其靶器官并发症的遗传学。两个队列均使用 Affymetrix 6.0 阵列对非裔美国受试者测量了 906,600 个 SNP 和 946,000 个 CNV 探针。在此应用中，我们建议估计群体遗传学的特征，评估现有 GWAS 分析工具的性能，并利用在 GENOA 的 1,854 名非裔美国人和 HyperGEN 的 1,802 名非裔美国人中鉴定的 SNP 和 CNV 进行血压和超声心动图特征的全基因组关联研究，具体目标如下： 目标 1. 表征拷贝数的分布 为了检测非裔美国人群体中的变异 (CNV)，我们将应用两种 CNV 识别方法：Canary 和 HelixTree CNAM，并使用 Affymetrix 6.0 阵列上的所有全基因组 SNP 探针和 CNV 探针。结果将使用来自 GENOA 和 HyperGEN 研究的两个独立的非裔美国人群体进行比较。目标 2：为了确定包含高血压、肥胖、左心室肥大和肾功能疾病易感位点证据的全基因组区域，我们将对每个非裔美国人群体进行分析，以确定相关的 CNV 和 SNP。为了减少误报，将针对多重测试和群体子结构调整关联，并进行复制比较。将进行汇总分析，通过结合 GENOA 和 HyperGEN 的结果来增强识别相关遗传变异的能力。目标 3：评估 为了了解现有基因型插补方法对非裔美国人的性能，我们将比较不同插补方法（MACH、IMPUTE 和 BEAGLE）在两个非裔美国人群体中的表现。为了提高非裔美国受试者的插补精度，我们将对插补精度较差的基因组区域进行测序，以了解 LD 结构并找出插补不准确的原因。 公共卫生相关性：人类基因组的遗传变异及其与心血管疾病和高血压的关联在非裔美国人群体中尚未得到充分研究。利用现有的906,600个SNP和946,000个拷贝数变异（CNV）探针的基因分型数据，以及之前收集的3,658名非裔美国人（1,854名GENOA和1,804名HyperGEN）的流行病学数据，我们将探讨群体遗传学（SNP和CNV）的特征，并对高血压危险因素和后遗症进行全基因组关联分析。群体遗传学的特征和显着的 CNV 效应将在来自 GENOA 和 HyperGEN 的两个独立的非裔美国人群体中复制。