Human Exome Sequencing in Six Well-Phenotyped NHLBI Cohorts

描述(由申请人提供)：全基因组关联(GWA)研究在识别可能包含导致心血管、肺和血液疾病风险的基因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研究确定的变异似乎只解释了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)大的和特征良好的种群的可用性和(2)大规模的DNA测序。我们建议在六个表型良好的NHLBI队列研究人员中建立一个多学科联盟-ARIC(社区动脉硬化风险)、CARDIA(青年冠状动脉风险发展)、CHS(心血管健康研究)、FHS(弗雷明翰心脏研究)、JHS(杰克逊心脏研究)和MESA(动脉粥样硬化的多种族研究)。该联盟为40,000多名参与者提供了心血管、肺和血液疾病的DNA和广泛的表型信息。该联盟包括来自四个民族(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，这有助于追踪罕见变异的传播并将其与表型相关联。共有30,517个联合体DNA样本立即可用于外显子组测序。高通量DNA测序和基因分型技术有许多方法。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)对来自六个队列的参与者的人类基因组中的所有外显子进行测序，以提高检测至少80%(高达100%)微小等位基因频率大于0.1%的变异的能力；(B)对优先表型进行统计遗传分析，以指导后续基因分型；(C)使用来自外显子组序列、DBGaP和1000基因组计划的数据，对所有符合条件的联合体样本中所有已识别的变异体(~100,000)进行基因分型；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(通过荟萃分析方法单独和联合)对心血管、肺和血液疾病表型的贡献。使用工作组协作模型，这些数据将被分析并在NHLBI表型的广泛范围内传播。这项申请代表着对研究的合理和高度创新的扩展，该研究已经在种族和地理上不同的人群中建立了一系列年龄范围内疾病的流行病学和遗传学基础。这项拟议的研究将极大地促进我们对疾病遗传基础的理解，并将为未来的功能研究提供基础。这些数据将存放起来，供更大的科学界使用，并将通过DBGaP访问。该项目是到目前为止由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能实现。 与公共卫生相关：心血管、肺和血液疾病是一种复杂但相互关联的疾病，由多种遗传和环境风险因素共同作用而产生。虽然已经发现基因组的许多区域可能包含风险变异，但几乎没有发现因果DNA变化。这项研究建议对整个人类基因组的编码区进行测序，以便识别或检测与心血管、肺和血液疾病风险相关的潜在原因变化，这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).