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: 8452339
• 负责人: Yan Sun
• 金额: $ 29.2万
• 依托单位: EMORY UNIVERSITY
• 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 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8452339
• 关键词: Genetics; Hypertension; Risk; Factors; Sequela

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）已经成功地确定了与高血压及其危险因素相关的基因组位点。然而，以前的GWAS是在欧洲血统人群中进行的，而不是在非洲血统人群中进行的。缺乏对非洲血统个体中现有单核苷酸多态性（snp）的推测或拷贝数变异（CNVs）及其与疾病关系的评估资源。国家心脏、肺和血液研究所（NHLBI）建议加强对非裔美国人群体中遗传变异（snp和CNVs）及其与常见疾病特征的关联的检查。非裔美国人是欧洲和非洲血统的混血儿。群体遗传学(例如；非裔美国人的连锁不平衡和等位基因频率)明显不同于他们的祖先。为了恰当地设计和实施非洲裔美国人心脏病的GWAS，必须在非洲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），以及必要的统计分析工具的性能，如基因型imputation和CNV调用。动脉病变遗传流行病学网络（GENOA）和HyperGEN都成立于1995年，目的是研究多民族兄弟姐妹中高血压及其靶器官并发症的遗传学。两个队列使用Affymetrix 6.0阵列对他们的非裔美国受试者测量了906,600个snp和946,000个CNV探针。在本申请中，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1854名来自GENOA的非洲裔美国人和1802名来自HyperGEN的非洲裔美国人的snp和CNVs进行血压和超声心动图特征的全基因组关联研究，具体目的如下：为了表征非裔美国人群体拷贝数变异（CNV）的分布，我们将使用全基因组SNP探针和Affymetrix 6.0阵列上的CNV探针，采用Canary和HelixTree CNAM两种CNV调用方法。研究结果将使用来自GENOA和HyperGEN研究的两个独立的非洲裔美国人进行比较。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位点证据的全基因组区域，我们将在每个非洲裔美国人群中进行分析，以确定相关的CNVs和snp。为了减少假阳性，将根据多重测试和种群亚结构调整关联，并比较复制。将进行汇总分析，通过结合GENOA和HyperGEN的结果来增加识别相关遗传变异的能力。目的3：评价