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

描述(申请人提供)：高血压(HT)或高血压(BP)占全球死亡人数的13.5%。与欧洲血统(EA)的人相比，非裔美国人(AA)经历了更高的HT发生率和相关的临床后果，以及发病年龄较早的更严重的HT，这些趋势在身体质量指数范围内保持不变。患病率、发病率和合并症的种族差异不能用公认的危险因素来解释，这表明腹主动脉相对于腹主动脉血压升高的病因学上的异质性。我们小组正在与大陆起源和遗传流行病学网络(COGINT)联盟一起领导对非洲血统人群中BP遗传决定因素的调查。Coent包括24个队列，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阶段II数据参考输入了19项研究，29,378名参与者，我们发现了3个新的BP基因区域，并提炼了5个先前在EA群体中发现的座位。国际HapMap数据由相对常见的变种组成。已经证明，许多等位基因频率在1-5%之间的低等位基因频率变异可以利用1000基因组联合会参考单倍型高质量地归因于。这项建议扩展了我们之前的分析，通过招募额外的AA队列、基于1000基因组计划参考的遗传变量以及最新的统计方法，测试了以前没有被评估过与BP特征关联的较低等位基因频率变量。我们的具体目标是：1)使用1,000个基因组输入的GWAs数据对联合群体队列的汇总统计数据进行单个SNP的荟萃分析；2)在每个联合队列中使用SKAT进行基于方差成分基因的分析，并随后对结果进行荟萃分析；3)使用个体水平的数据和来自可信参与者的汇总统计数据来评估最近对已知和新的BP基因座的标准变异进行的选择性扫描是否有助于观察到AA和EA群体之间的平均BP差异。我们的建议是高度可行的，成本效益高，功能强大，并利用了令人信服的财团合作的现有资源，将代表着迄今为止在AA人群中进行的最大规模的BP基因研究。我们的研究团队有参与和领导大型心血管特征荟萃分析的经验，并且支持这一项目的设备和设施已经到位。我们的团队将包括一个独立的分析小组，负责对荟萃分析结果进行独立验证。此外，我们将能够积累大量样本，利用现有资源对BP决定因素进行最大规模的系统调查，精细绘制BP突变图谱，并探索最近的自然选择，这可能部分解释了EA和AA之间始终观察到的BP特征的差异。这项研究有可能成为HT和BP遗传学领域的一项有影响力的研究，并无疑将激励R01提交后续报告，并精细绘制已识别的基因区域。

DESCRIPTION (provided by applicant): 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.