A Multi-Ethnic Study of Gene-Lifestyle Interactions in Cardiovascular Traits

描述（由申请人提供）：心血管疾病（CVD）及其风险因素（如血压（BP）和血脂）的管理仍然是一个主要的公共卫生问题。因此，了解这些性状的遗传基础以及环境如何调节影响这些性状的遗传效应非常重要，因为它可能为干预措施提供重要线索。在过去的几年里，全基因组关联研究（GWAS）的出现彻底改变了该领域，在识别与许多常见复杂疾病和疾病相关性状（包括心血管性状）相关的数百种常见遗传变异方面取得了快速进展。尽管取得了这些非凡的成就，但大多数已确定的遗传变异的效应大小都很小，风险增量相对较小，而且在大多数情况下，只能解释小部分的性状变异。人们越来越认识到，对常见变异（通常影响较小）的主要影响的近乎排他性的关注已成为识别这些疾病特征背后的其他基因（影响较大）的障碍。这些发现工作需要更复杂的方法，如基因-环境相互作用，对相关性状的多效性效应的分析，以及途径分析。 虽然文献中报道了涉及基因-环境相互作用的重要研究，但这是第一个系统的、有力的大型财团级努力，用于使用非常大的样本量系统地评估基因-生活方式相互作用。我们建议调查基因-生活方式的相互作用，遗传结构的相关性状与多效性分析，和途径分析，每一个作为一种手段，揭示更多的原因不明的遗传变异的BP和血脂。我们将通过利用现有多种族研究/队列的非凡资源来做到这一点，这些研究/队列具有常见（GWAS）和罕见变异（外显子组芯片）的表型，相关生活方式数据和密集基因型数据。我们的应用涉及25个队列，其中GWAS数据涉及90，673名欧洲裔美国人，34，543名非洲裔美国人，13，174名西班牙裔美国人和12，375名亚洲人，总人数为N= 150，765，其中外显子组芯片数据约占样本的61%。将从两个大型联盟（Global BP Genetics或GBPgen和Global Lipids Genetics Consortium或GLGC）中寻求重复研究，总样本量为160，958例受试者。这将是迄今为止在发现或复制中调查总样本量超过300，000的相互作用的最重要努力。及时的资金可以维持通过将这种应用组合在一起所产生的巨大势头，这最终可能导致新的治疗方法，从而可能影响临床实践。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) and management of its risk factors such as blood pressure (BP) and plasma lipids continue to be a major public health problem. Therefore, understanding the genetic basis of these traits and how the environment modulates genetic effects in influencing these traits is important because it may provide important clues for interventions. Over the past several years, the advent of Genome-Wide Association Studies (GWAS) has revolutionized the field with rapid progress in identifying hundreds of common genetic variants associated with many common complex diseases and disease-related traits including cardiovascular traits. Despite these extraordinary accomplishments, most of the identified genetic variants have small effect sizes, confer relatively small increments of risk and, for the most part, explain only small proportions of the trait variance. It is increasingly recognized that the near-exclusive focus on main effects of common variants (which generally have small effects) has become a barrier to the identification of additional genes (with larger effects) underlying these disease traits. These discovery efforts need more sophisticated approaches such as gene- environment interactions, analysis of pleiotropic effects on correlated traits, and pathway analysis. Although important research involving gene-environment interactions is being reported in the literature, this is the first systematic, well-powered large consortium-level effort for systematically evaluating gene- lifestyle interactions using very large sample sizes. We propose to investigate gene-lifestyle interactions, the genetic architecture of correlated traits with pleiotropy analysis, and pathway analysis, each as a means for uncovering more of the unexplained genetic variance in BP and lipids. We will do this by leveraging the extraordinary resources of existing multi-ethnic studies/cohorts that have the phenotypes, relevant lifestyle data and dense genotype data on common (GWAS) as well as rare variants (Exome chip). Our application involves 25 cohorts with GWAS data on 90,673 European Americans, 34,543 African Americans, 13,174 Hispanic Americans, and 12,375 Asians, for an overall total of N=150,765, with Exome Chip data on about 61% of the samples. Replication will be sought from two large consortia with an aggregate sample size of 160,958 subjects (Global BP Genetics or GBPgen, and Global Lipids Genetics Consortium or GLGC). This would represent the most significant effort to date to investigate interactions with an aggregate sample size over 300,000 in either discovery or replication. Timely funding can sustain the great momentum generated by putting together this application, which could ultimately lead to novel therapeutic approaches thus potentially impacting clinical practice.