Rare variants and NHLBI traits in deeply phenotyped cohorts

深度表型队列中的罕见变异和 NHLBI 特征

• 批准号: 8683958
• 负责人: Bruce M Psaty
• 金额: $ 76.28万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8683958
• 关键词: Address; Aging; Amino Acid Sequence; Architecture; Atherosclerosis; Atrial Fibrillation; Biological; Biology; Blood; Blood Pressure; Body Composition; Candidate Disease Gene; Cardiovascular system; Chronic Kidney Failure; Code; Cohort Studies; Collaborations; Committee Members; Communities; Complex; Coronary artery; Data; Data Analyses; Development; Diabetes Mellitus; Disease; Elements; Environment; Epidemiology; Epigenetic Process; Erythrocytes; Ethnic group; Event; Exons; Family; Fatty Acids; Framingham Heart Study; Funding; Future; Gene Frequency; Genetic; Genome; Genomics; Genotype; Health; Heart; Hematology; Hemostatic function; Heritability; Individual; Inflammation; Institutes; Jackson Heart Study; Lead; Lipids; Lung; Measures; Meta-Analysis; Methods; Minor; National Heart, Lung, and Blood Institute; Neurology; Obesity; Participant; Pathway interactions; Persons; Phenotype; Population; Predisposition; Price; Publications; RNA Splicing; Recommendation; Research; Research Personnel; Residual state; Risk; Risk Factors; Role; Sample Size; Site; Source; Source Code; Systems Biology; Technology; Ursidae Family; Variant; aging gene; base; cohort; cost; design; disorder risk; exome sequencing; genetic association; genetic resource; genetic variant; genome wide association study; insight; novel; organizational structure; prospective; protein structure; public health relevance; pulmonary function; rare variant; symposium; therapeutic target; trait; working group; young adult

DESCRIPTION (provided by applicant): Although genome-wide association studies (GWAS) have identified statistically significant associations of common genetic variants with a variety of complex diseases and risk factors, these common variants typically explain only 5-10% of the genetic contribution to the phenotypic variance. The residual genetic variance, "the missing heritability," may have several sources and is in part attributed to rare variants. As a means of performing association studies in large populations, a panel of variants derived from the exome sequencing of over 12,000 subjects has been used to create an Illumina Infinium genotyping array, the ExomeChip, which features non-synonymous, non-sense, and splice-site coding-region rare or infrequent variants. The analytic challenges and the sample size requirements for the high-quality analysis of these rare coding-region variants will require novel organizational structures and collaborations. In the GWAS era, one of the most successful and productive collaborations has been the CHARGE Consortium, which facilitated prospectively planned GWAS meta-analyses of multiple phenotypes among large cohort studies. The original five CHARGE cohorts and four collaborating cohorts have jointly-called ExomeChip genotype data on more than 50,000 participants. While the cohorts have been able to reallocate funding (with Institute approval) to generate the rare variant data, there are no additional funds available in existing sources to address analytic issues, to coordinate efforts, or to implement the analysis of the ExomeChip data. The CHARGE collaboration, which takes advantage of the hundreds of millions of dollars invested in these cohort studies, represents a unique resource for genetic studies. The phenotype-specific Working Groups take the lead in choosing and harmonizing phenotypes. The CHARGE Analysis Committee members not only provide recommendations for analytic methods, but they also solve analytic problems, conduct cohort-specific analysis, and implement consortium- wide prospectively planned meta-analyses. In the GWAS era, these methods and this organizational structure enabled the CHARGE investigators to accelerate the discovery of genetic association for common variants. Using the available ExomeChip coding-region genotype data from 9 well-phenotyped cohorts, the primary aim is to discover novel candidate genes and putative functional variants for high-priority heart, lung and blood phenotypes in multi-ethnic cohorts. The main activities include the selection of high-priority phenotypes, the appraisal and dissemination of analytic methods, the conduct of rare-variant analyses within each cohort, the meta-analysis of cohort-specific findings, both within and between ethnic groups, analysis of family data, pathway analyses, efforts to identify analytic problems, publication of findings, and the public release of source code and methods appraisals. We expect to complete at least 3-4 major analyses each year. The findings will be used to better understand biological pathways that may identify therapeutic targets.

描述（由申请人提供）：尽管全基因组关联研究（GWAS）已经确定了常见遗传变异的统计学意义与多种 这些常见变体的复杂疾病和危险因素通常仅解释了对表型差异的遗传贡献的5-10％。残留的遗传差异“缺失的遗传力”可能有多种来源，部分归因于稀有变体。作为在大量人群中进行关联研究的一种手段，已使用超过12,000名受试者的外显子组测序得出的一组变体，用于创建一个Illumina Infinium Infinium基因分型阵列，Exomechip，其具有非同义词，非sense和splice Sote Sote-Site Soding Soding-Site-Site-Site-Site-Site-Soting-Soting-Region-Region-Region稀有或Infrequent或Infrequend rovents。对这些稀有编码区域的高质量分析的分析挑战和样本量要求将需要新颖的组织结构和协作。在GWAS时代，最成功，最有生产力的合作之一是Charge Consortium，这促进了大型队列研究中多种表型的前瞻性计划的GWAS荟萃分析。最初的五个指控队列和四个合作的同类群体已共同针对50,000多名参与者进行了外观基因型数据。尽管同类人群已经能够重新分配资金（并获得研究所的批准）来生成稀有的变体数据，但现有资源中没有其他资金可用于解决分析问题，协调努力或实施分析的分析 Exomehip数据。费用合作利用了这些队列研究投资的数亿美元，它代表了遗传研究的独特资源。特定于表型的工作组在选择和协调表型方面占据主导地位。指控分析委员会成员不仅为分析方法提供建议，而且还解决了分析问题，进行了特定于同类的分析并实施了群体的前瞻性荟萃分析。在GWAS时代，这些方法和这种组织结构使指控调查人员能够加速对常见变体的遗传关联的发现。使用来自9个良好型人群的可用外科编码区域基因型数据，主要目的是发现多种族裔人群中高优先性心脏，肺和血液表型的新型候选基因和推定的功能变体。主要活动包括选择高优先级表型，分析方法的评估和传播，每个队列中的稀有分析的进行，族裔群体内部和族裔的荟萃分析，族裔群体内部和族之间的荟萃分析，家庭数据分析，途径分析，努力，努力，努力确定了范围的范围，并宣布了范围的范围，并释放了范围，并释放了范围，并释放了范围的范围，以及这些范围的宣布，以及宣布的范围，以及宣布的范围，以及宣布的范围，以及这些范围的范围，以及这些范围的范围，以及宣布的范围。我们预计每年至少完成3-4个主要分析。这些发现将用于更好地了解可能识别治疗靶标的生物学途径。