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

项目摘要 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 (AAs)HT和相关临床后果的发生率高于欧洲血统（EA）人群， 以及更严重的HT与更早的发病年龄，这些趋势保持在身体的范围内， 质量指数值。患病率、发病率和合并症的种族差异不能很好地解释- 公认的风险因素，并表明相对于EA，AA之间血压升高的病因异质性。我们 该小组正在领导对非洲血统人群中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 有39，397名参与者具有可用的全基因组关联研究（GWAS）数据。在以前的一项研究中， 我们使用HapMap II期数据参考对19项研究（29，378例受试者）进行了估算，我们发现3项 新的BP基因区域和改进的5个位点先前确定的EA人口。国际HapMap 数据由相对常见的变量组成。已经证明，许多低等位基因频率变异 等位基因频率在1-5%之间，可以使用1000个基因组联盟进行高质量的插补 参考单倍型。该建议通过测试较低的等位基因频率变异来扩展我们先前的分析 先前没有通过招募额外的AA队列来评估与BP性状的关联， 基于1000个基因组项目参考和最先进的统计数据， 接近。我们的具体目标是：1）对汇总统计的单个SNP进行荟萃分析， 使用1，000个基因组插补的GWAS数据的COGENT联盟队列; 2）进行方差分量 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BP位点的站立变异进行的选择性扫描有助于观察到的差异 AA和EA人群之间的平均血压。我们的建议是高度可行的，成本效益高，功能强大， 利用COGENT联盟合作的现有资源，并将代表最大的遗传 迄今为止，AA人群中的BP研究。我们的调查员团队具有参与和领导 对心血管特征的大型荟萃分析以及设备和设施已经到位，以支持这一点 项目我们的团队将包括一个独立的分析小组，负责独立核实 Meta分析结果。此外，我们将能够通过利用现有的 资源进行最大的BP决定因素的系统调查，BP突变的精细映射， 以及对最近自然选择的探索，这可能部分解释BP性状的差异。 在EA和AA之间观察。这项研究有可能成为HT和BP领域有影响力的研究 这无疑将激励R 01提交后续和精细定位已鉴定的基因区域。

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.