COGENT consortium meta-analysis of blood pressure in African ancestry cohorts

COGENT 联盟对非洲血统人群血压的荟萃分析

• 批准号: 8625046
• 负责人: Todd L Edwards
• 金额: $ 13.43万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8625046
• 关键词: Accounting; African; African American; Age of Onset; Alleles; Architecture; Arts; Asians; Blood Pressure; Body mass index; Cardiovascular system; Cessation of life; Chronic Disease; Clinical; Collaborations; Collection; Comorbidity; Data; Data Set; Equipment; European; Exploratory/Developmental Grant; Gene Components; Gene Frequency; Genes; Genetic; Genetic Determinism; Genetic Variation; Genome; Haplotypes; Heterogeneity; Human; Hypertension; Incidence; Individual; International; Investigation; Maps; Meta-Analysis; Methods; Mutation; NIH Program Announcements; Natural Selections; Participant; Persons; Phase; Population; Prevalence; Public Health; Publishing; Recording of previous events; Recruitment Activity; Relative (related person); Research; Research Personnel; Resources; Risk; Risk Factors; Sample Size; Staging; Testing; Variant; base; cardiovascular disorder epidemiology; cohort; cost; eligible participant; experience; follow-up; genetic epidemiology; genetic variant; genome wide association study; insight; novel; public health relevance; racial difference; statistics; trait; trend

PROJECT SUMMARY Hypertension (HT) or elevated blood pressure (BP) account for 13.5% of deaths worldwide. African Americans (AAs) experience higher rates of HT and related clinical consequences than European ancestry (EA) persons, as well as more severe HT with earlier age-of-onset, and these trends are maintained over the range of body mass index values. Racial differences in prevalence, incidence, and co morbidities are not explained by well- recognized risk factors and suggest etiological heterogeneity for elevated BP among AAs relative to EAs. Our group is leading the investigation of the genetic determinants of BP in African-ancestry populations with the Continental Origins and Genetic Epidemiology Network (COGENT) consortium. COGENT includes 24 cohorts with 39,397 participants with available genome-wide association study (GWAS) data. In a previous study of 19 studies with 29,378 participants we imputed using the HapMap Phase II data reference, we discovered 3 novel BP gene regions and refined 5 loci previously identified in the EA population. The International HapMap data consists of relatively common variants. It has been demonstrated that many low allele frequency variants with allele frequencies between 1-5% can be imputed with high quality using the 1000 Genomes Consortium reference haplotypes. This proposal extends our previous analysis by testing lower allele frequency variants that have not been previously evaluated for association with BP traits through recruiting additional AA cohorts, imputing genetic variants based on the 1000 Genomes Project reference, and state-of-art statistical approaches. Our Specific Aims are: 1) Conduct a meta-analysis at individual SNPs of summary statistics from COGENT consortium cohorts using 1,000 Genomes-imputed GWAS data; 2) Conduct variance component gene-based analyses using SKAT within each COGENT consortium cohort, and subsequent meta-analysis of results; 3) Use individual level data and summary statistics from COGENT participants to evaluate whether recent selective sweeps on standing variation in known and novel BP loci contributes to the observed disparity in average BP between AA and EA populations. Our proposal is highly feasible, cost-efficient, powerful, and employs existing resources from the COGENT consortium collaboration and will represent the largest genetic study of BP in the AA population to date. Our team of investigators has experience participating in and leading large meta-analyses of cardiovascular traits and the equipment and facilities are in place to support this project. Included in our team will be an independent analysis group, tasked with independent verification of meta-analysis results. In addition, we will be able to accumulate a large sample size by utilizing existing resources to conduct the largest systematic investigation of BP determinants, fine mapping of BP mutations, and exploration of recent natural selection that may explain in part the disparities in BP traits consistently observed between EAs and AAs. This study has the potential to be an impactful study in the field of HT and BP genetics and will undoubtedly motivate R01 submissions to follow-up and fine-map identified gene regions.

项目概要 高血压 (HT) 或血压升高 (BP) 占全球死亡人数的 13.5%。非裔美国人 (AA) 比欧洲血统 (EA) 人经历更高的 HT 发生率和相关临床后果， 以及更严重的 HT 发病年龄更早，并且这些趋势在整个身体范围内保持不变 质量指数值。患病率、发病率和合并症的种族差异无法用很好的解释 公认的危险因素，并表明 AA 相对于 EA 血压升高的病因学异质性。我们的 该小组正在领导非洲血统人群中 BP 遗传决定因素的调查 大陆起源和遗传流行病学网络 (COGENT) 联盟。 COGENT 包括 24 个队列 共有 39,397 名参与者拥有可用的全基因组关联研究 (GWAS) 数据。在之前的一项研究中 我们使用 HapMap II 期数据参考对 19 项涉及 29,378 名参与者的研究进行了估算，我们发现 3 新的 BP 基因区域和先前在 EA 群体中发现的精炼 5 个基因座。国际单体型图 数据由相对常见的变体组成。已经证明许多低等位基因频率变异 使用 1000 Genomes Consortium 可以对等位基因频率在 1-5% 之间进行高质量估算 参考单倍型。该提案通过测试较低等位基因频率变异扩展了我们之前的分析 之前没有通过招募额外的 AA 队列来评估与 BP 特征的关联， 根据 1000 个基因组计划参考和最先进的统计数据估算遗传变异 接近。我们的具体目标是： 1) 对各个 SNP 的汇总统计数据进行荟萃分析 COGENT 联盟队列使用 1,000 个基因组估算的 GWAS 数据； 2) 行为差异成分 在每个 COGENT 联盟队列中使用 SKAT 进行基于基因的分析，以及随后的荟萃分析 结果; 3) 使用 COGENT 参与者的个人水平数据和汇总统计数据来评估是否 最近对已知和新的 BP 位点的固定变异的选择性扫描导致了观察到的差异 AA 和 EA 人群之间的平均血压。我们的建议是高度可行的、具有成本效益的、强大的、 利用 COGENT 联盟合作的现有资源，将代表最大的遗传资源 迄今为止对 AA 人群中 BP 的研究。我们的研究团队拥有参与和领导的经验 对心血管特征的大型荟萃分析以及支持这一点的设备和设施已经到位 项目。我们的团队将包括一个独立的分析小组，其任务是独立验证 荟萃分析结果。此外，我们将能够利用现有的数据积累大量样本。 进行最大规模的 BP 决定因素系统研究、BP 突变精细定位、 以及对最近自然选择的探索，这可能在一定程度上解释了血压特征的差异 在 EA 和 AA 之间观察到。这项研究有可能成为 HT 和 BP 领域的一项有影响力的研究 遗传学，无疑将激励 R01 提交后续和精细图谱确定的基因区域。