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

描述（由申请人提供）：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）的HT和相关临床后果的发生率高于欧洲血统（EA）的人，以及更严重的HT与更早的发病年龄，这些趋势保持在体重指数值的范围内。患病率、发病率和合并症的种族差异不能用公认的风险因素来解释，表明AA相对于EA之间BP升高的病因异质性。我们的小组正在与大陆起源和遗传流行病学网络（COGENT）联盟一起领导对非洲血统人群中BP遗传决定因素的调查。COGENT包括24个队列，39，397名参与者，具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期数据参考进行了19项研究，涉及29，378名参与者，我们发现了3个新的BP基因区域，并改进了先前在EA人群中确定的5个位点。国际HapMap数据由相对常见的变异组成。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体可以使用1000个基因组联盟参考单倍型以高质量插补。该提案通过招募额外的AA队列，基于1000个基因组项目参考和最先进的统计方法估算遗传变异，测试先前未评估与BP性状相关性的较低等位基因频率变异，扩展了我们先前的分析。我们的具体目标是：1）使用1，000个基因组插补的GWAS数据对来自COGENT联盟队列的汇总统计的单个SNP进行荟萃分析; 2）在每个COGENT联盟队列内使用SKAT进行基于方差分量基因的分析，并随后对结果进行荟萃分析;第三章使用COGENT参与者的个体水平数据和汇总统计量，评估最近对已知和新的立位变异的选择性扫描是否BP基因座有助于AA和EA人群之间的平均血压观察到的差异。我们的建议是高度可行的，成本效益高，功能强大，并利用现有的资源，从COGENT财团合作，并将代表最大的遗传研究BP在AA人口的日期。我们的研究人员团队有参与和领导心血管特征大型荟萃分析的经验，并且设备和设施已经到位，以支持该项目。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，我们将能够积累一个大的样本量，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，并探索最近的自然选择，这可能部分解释了EA和AA之间一致观察到的BP性状差异。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，无疑将激励R 01提交后续和精细定位已识别的基因区域。

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.