Human Exome Sequencing in Six Well-Phenotyped NHLBI Cohorts

描述（由申请人提供）：全基因组关联（GWA）研究在识别可能含有导致心血管、肺和血液疾病风险的遗传变异的区域方面取得了很大进展。尽管取得了这些成功，但通过GWA研究发现的变异似乎只能解释观察到的疾病风险的一小部分。该项目解决了两个研究需求-（1）大规模和良好表征的人群的可用性和（2）大规模DNA测序。我们建议在六个表型良好的NHLBI队列的研究者中建立一个多学科联盟- ARIC（社区动脉粥样硬化风险），CARDIA（年轻人冠状动脉风险发展），CHS（心血管健康研究），FHS（心脏病研究），JHS（杰克逊心脏研究）和梅萨（多种族动脉粥样硬化研究）。该联盟为超过40，000名参与者提供了心血管，肺部和血液疾病的DNA和广泛的表型信息。该联盟包括来自四个种族（欧洲，非洲，西班牙裔和亚洲）以及欧洲，非洲和西班牙裔家庭的参与者，可用于跟踪罕见变异的传播并将其与表型相关联。共有30，517个联盟DNA样本可立即用于外显子组测序。 存在许多高通量DNA测序和基因分型技术的方法。虽然测序、基因分型和分析的决定将由项目指导委员会指导，但我们建议（a）对六个队列中每个队列的参与者进行人类基因组的所有外显子测序，以提高检测至少80%（和高达100%）的具有大于0.1%的次要等位基因频率的变体;（B）对优先表型进行统计遗传分析，以指导后续基因分型;（c）对所有鉴定的变异体进行基因分型使用来自外显子组序列、dbGaP和1000个基因组计划的数据，在所有合格的联盟样品中，在人类外显子组中存在约100，000个;以及（d）继续对联盟样本进行外显子组和全基因组测序，并进行统计遗传分析，以确定队列中常见和罕见变异（单独和通过荟萃分析方法联合）对心血管、肺部和血液疾病表型的贡献。使用工作组协作模型，这些数据将在广泛的NHLBI表型中进行分析和传播。该应用程序代表了研究的逻辑和高度创新的扩展，该研究已经在种族和地理上不同的人群中建立了疾病的流行病学和遗传基础。这项研究将极大地推进我们对疾病遗传基础的理解，并为未来的功能研究奠定基础。这些数据将被保存，供更大的科学界使用，并将通过dbGaP访问。该项目是迄今为止由NHLBI支持的各个队列进行的研究的延伸，只有通过这一努力才有可能。 公共卫生相关性：心血管、肺和血液疾病代表了一种复杂但相互关联的疾病谱，这些疾病是由多种遗传和环境风险因素作用引起的。虽然基因组的许多区域已被确定可能含有风险变异，但很少有因果DNA变化被确定。这项研究建议对整个人类基因组的编码区进行测序，以识别或检测与心血管、肺和血液疾病风险相关的潜在因果变化，从而可能导致更好的风险预测、干预和治疗（预防）。

DESCRIPTION (provided by applicant): Genome-wide association (GWA) studies have made great progress in the identification of regions that are likely to contain genetic variants contributing to the risk of cardiovascular, lung and blood diseases. Despite these successes, variants identified through GWA studies appear to explain only a small fraction of the observed disease risk. This project addresses two needs of research - (1) the availability of large and well- characterized populations and (2) large-scale DNA sequencing. We propose to establish a multi-disciplinary Consortium among investigators of six well-phenotyped NHLBI cohorts - ARIC (Atherosclerosis Risk in Communities), CARDIA (Coronary Artery Risk Development in Young Adults), CHS (Cardiovascular Health Study), FHS (Framingham Heart Study), JHS (Jackson Heart Study), and MESA (Multi-Ethnic Study of Atherosclerosis). This Consortium provides over 40,000 participants with DNA and extensive phenotype information across the spectrum of cardiovascular, lung and blood disorders. The Consortium includes participants from four ethnicities (European, African, Hispanic and Asian) as well as families of European, African and Hispanic descent, useful for tracking transmission of rare variants and correlating them with phenotypes. A total of 30,517 Consortium DNA samples are immediately available for exome sequencing. There are many approaches to high throughput DNA sequencing and genotyping technologies. While decisions on sequencing, genotyping and analyses will be guided by the project Steering Committee, we propose to (a) sequence all exons in the human genome on participants from each of the six cohorts to enhance the ability to detect at least 80% (and up to 100%) of the variants with minor allele frequency greater than 0.1%; (b) conduct statistical genetic analyses on priority phenotypes to guide follow-up genotyping; (c) genotype all identified variants (~100,000) in the human exome in all eligible Consortium samples using data from the exome sequence, dbGaP and 1000 Genomes Project; and (d) continue to perform exome and whole genome sequencing on Consortium samples and conduct statistical genetic analysis to define the contributions of common and rare variants in the cohorts (individually and jointly through meta-analytic approaches) to phenotypes of cardiovascular, lung and blood diseases. Using a Working Group collaborative model, these data will be analyzed and disseminated across a broad spectrum of NHLBI phenotypes. This application represents a logical and highly innovative extension to research that has established the epidemiologic and genetic basis of disease over a range of ages in ethnically and geographically diverse populations. The proposed research will greatly advance our understanding of the genetic basis of disease and will provide a foundation for future functional studies. These data will be deposited for use by the greater scientific community and will be accessible through dbGaP. The project represents an extension of the research performed to date by the individual NHLBI-supported cohorts and will be possible only through this effort. PUBLIC HEALTH RELEVANCE: Cardiovascular, lung and blood disorders represent a complex, but interrelated, spectrum of conditions that arises from the action of multiple genetic and environmental risk factors. Although many regions of the genome have been identified that likely contain risk variants, few causal DNA changes have been identified. This research proposes to perform sequencing of coding regions across the human genome in order to identify or detect the potential causal changes that are associated with risk for cardiovascular, lung and blood diseases that may lead to better risk prediction, intervention and therapeutics (prevention).