Genetics of Hypertension Risk Factors and Sequela in African Americans

描述(由研究人员提供)：本申请涉及广泛的挑战领域(08)基因组学和特定挑战主题，08-HL-104：评估非裔美国人的基因变异并确定其对疾病的影响。近年来，全基因组关联研究成功地确定了与高血压及其危险因素相关的基因组基因座。然而，以前的GWA是在欧洲血统的人口中进行的，而不是非洲血统的人口。缺乏资源来估算现有的单核苷酸多态(SNPs)或评估拷贝数变异(CNV)及其与非洲血统个人疾病的关系。国家心肺和血液研究所(NHLBI)建议更加重视对非裔美国人队列中的遗传变异(SNPs和CNV)及其与常见疾病特征的相关性的检查。非裔美国人是既有欧洲血统又有非洲血统的混血儿。群体遗传学(如：非裔美国人的连锁不平衡和等位基因频率)明显不同于他们的任何一个祖先。为了恰当地设计和实施非裔美国人心脏病的GWA，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(SNP)和拷贝数变异(CNV)，以及必要的统计分析工具的性能，如基因归因法和CNV呼叫。动脉病遗传流行病学网络(Genoa)和HyperGEN都是在1995年发起的，目的是研究多民族同胞中高血压及其靶器官并发症的遗传学。这两个队列都使用Affymetrix 6.0阵列在他们的非裔美国人受试者身上测量了906,600个SNPs和946,000个CNV探针。在这项应用中，我们建议估计群体遗传学特征，评估现有GWAS分析工具的性能，并利用从热那亚1,854名非洲裔美国人和来自HyperGEN的1,802名非洲裔美国人身上发现的SNP和CNV，对血压和超声心动图特征进行全基因组关联研究，具体目标如下：目的1.为了表征拷贝数变异(CNV)在非裔美国人群体中的分布，我们将应用两种CNV调用方法，Canary和HelixTree CNAM，使用所有基因组范围的SNP探针和Affymetrix 6.0阵列上的CNV探针。结果将使用热那亚和HyperGEN研究中的两个独立的非裔美国人进行比较。目的2：为了确定包含高血压、肥胖、左心室肥厚和肾功能疾病易感基因的全基因组区域，我们将在每个非裔美国人群体中进行分析，以确定相关的CNV和SNPs。为了减少假阳性，将针对多个测试和总体子结构调整关联，并比较复制。将进行汇集分析，通过结合热那亚和HyperGEN的结果来增加识别相关遗传变异的能力。目标3：评估 为了比较现有的非裔美国人基因分配方法的性能，我们将比较不同的分配方法(Mach、Inpute和Beagle)在两个非裔美国人群体中的性能。为了提高非裔美国人受试者的归因率，我们将对归因率较低的基因组区域进行测序，以了解LD结构并找出导致归因率不准确的原因。 公共卫生相关性：在非裔美国人群体中，人类基因组中的遗传变异及其与心血管疾病和高血压的关联研究不足。利用现有的906,600个SNPs和946,000个拷贝数变异(CNV)探针的基因分型数据，以及先前收集的3658名非裔美国人(1,854名热那亚人和1,804名HyperGEN)的流行病学数据，我们将调查人群遗传学特征(SNPs和CNV)，并对高血压危险因素和后遗症进行全基因组关联分析。人口遗传学的特点和显著的CNV效应将在热那亚和HyperGEN的两个独立的非裔美国人群体中复制。

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.