Targeted Sequencing Study of GWAS-implicated Blood Pressure Loci

项目概要（研究项目1） 这项研究的总体目标是确定新的基因和功能性遗传变异 与血压（BP）相关的9个位点，在最近的亚洲研究中获得了全基因组意义， 遗传流行病学网络（阿根）-使用next的BP全基因组关联研究（GWAS）荟萃分析 代测序技术。这项研究将在5,000名汉族人中进行 亚洲心血管疾病国际合作研究（InterASIA）InterASIA 提供了一个关于BP相关表型的非凡资源以及足够数量的DNA， 储存在我们的实验室用于基因研究在拟议的研究中，我们将发现新的功能变体 通过对300名InterASIA参与者中9个GWAS相关基因座的连续基因组区域进行深度测序， 平均动脉压（MAP）最高，300名参与者未服用降压药物， 最低的MAP这种不可知的测序方法将使我们能够检查基因间变异， 潜在重要但尚未充分理解的调控功能以及这些基因座上的所有15个已知基因， 平均每个跨越155个碱基。生物信息学工具将用于过滤大量的 发现变异，优先考虑那些预测功能相关性。为了最大化统计功效， 变体将使用以下方法进行分组：1）不可知滑动窗口方法， 跨越整个基因座的相邻和重叠片段;以及2）基于生物学的方法， 已知功能单位（例如保守区域或基因）的罕见变异。我们会用最先进的统计数据 方法来检查聚合分析中罕见变异体的集体效应。一种新型低频和 将使用传统的单标记分析分别检查常见变异。我们将基因分型 在剩下的4，400名InterASIA参与者中选出200种最有希望的新变异，并测试相关性 在5，000名（4，400名基因型+ 600名测序）InterASIA参与者中，每个变体与BP之间的关系。 我们将在10，000名汉族人的独立随机样本中复制25种最有希望的变异中的每一种。 中国参与者。此外，我们将利用现有的GWAS、全外显子组和表型数据， 在基因型和表型数据库中，评估25个最有希望的 在多达15，076名非洲裔美国人和30，821名欧洲人的大型人群样本中， 美国参与者然后将进行特定学科和总体荟萃分析。这些发现 可能具有重要的临床和公共卫生意义。通过帮助阐明 潜在的BP调节，这些发现可用于开发新的基于基因的策略， 预防和治疗高血压。此外，拟议的COBRE初级项目所获得的经验 研究员应该成为她成为独立研究员的重要垫脚石。

Project Summary (Research Project 1) The overall objective of the proposed study is to identify novel genes and functional genetic variants associated with blood pressure (BP) at 9 loci which attained genome-wide significance in the recent Asian Genetic Epidemiology Network (AGEN)-BP genome-wide association study (GWAS) meta-analysis using next generation sequencing technology. The proposed study will be carried out among 5,000 Han Chinese participants of the International Collaborative Study of Cardiovascular Disease in Asia (InterASIA). InterASIA provides an extraordinary resource on BP-related phenotypes as well as sufficient quantities of DNA already stored at our laboratories for genetic research. In the proposed study, we will discover novel functional variants by deep sequencing contiguous genomic regions of 9 GWAS-implicated loci among 300 InterASIA participants with the highest mean arterial pressure (MAP) and 300 participants not taking antihypertension medication with the lowest MAP. This agnostic sequencing approach will allow us to examine intergenic variants with potentially important but not well-understood regulatory functions as well as all 15 known genes at these loci, which span an average of 155 kilobases each. Bioinformatic tools will be used to filter the large number of discovered variants, prioritizing those with predicted functional relevance. To maximize statistical power, rare variants will be grouped using: 1) an agnostic sliding window approach which aggregates rare variants in adjacent and overlapping segments across the entire loci; and 2) a biology-based approach which aggregates rare variants by known functional units (e.g. conserved region or gene). We will use state-of-the-art statistical methods to examine the collective effects of rare variants in aggregate analyses. Novel low-frequency and common variants will be examined separately using traditional single-marker analyses. We will genotype the 200 most promising novel variants among the remaining 4,400 InterASIA participants and test the association between each variant and BP among the 5,000 (4,400 genotyped + 600 sequenced) InterASIA participants. We will replicate each of the 25 most promising variants in an independent random sample of 10,000 Han Chinese participants. In addition, we will leverage existing GWAS, whole-exome, and phenotype data available in the database of Genotypes and Phenotypes to assess the trans-ethnic relevance of the 25 most promising BP variants within large, population-based samples of up to 15,076 African-American and 30,821 European- American participants. Ancestry-specific and overall meta-analyses will then be carried out. These findings may have important clinical and public health implications. By helping to elucidate the biological pathways underlying BP regulation, these findings may be used to develop novel gene-based strategies for the prevention and treatment of hypertension. Furthermore, the experience gained by the proposed COBRE junior faculty investigator should serve as an important stepping stone to her success as an independent researcher.