Probing The Dark Matter of the Genome in the NHLBI Family Heart Study

在 NHLBI 家庭心脏研究中探索基因组的暗物质

• 批准号: 9096206
• 负责人: Michael A. Province
• 金额: $ 74.55万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-22 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096206
• 关键词: Accounting; Address; African American; Alleles; American; Architecture; Atherosclerosis; BRCA1 gene; Biology; Cardiovascular Diseases; Cardiovascular system; Case-Control Studies; Cells; Child; Cholesterol; Code; Cohort Studies; Complex; Coronary heart disease; Cystic Fibrosis Transmembrane Conductance Regulator; DNA Resequencing; Data; Diabetes Mellitus; Disease; Disease Pathway; Dyslipidemias; Epidemiologic Studies; European; Event; Exons; Family; Family Sizes; Family Study; Gene Frequency; Genes; Genetic; Genome; Genotype; Goals; Haplotypes; Heart; Heart Diseases; Heritability; High Density Lipoproteins; Human; Human Genome; Hypertension; Individual; Inflammation; Insulin Resistance; Knowledge; Lead; Letters; Life; Lipids; Measures; Medical; Mendelian disorder; Modeling; Mutation; National Heart, Lung, and Blood Institute; Nature; Noise; Nucleic Acid Regulatory Sequences; Obesity; Parents; Pathway interactions; Pattern; Penetrance; Phenotype; Population; Population Control; Prevalence; Production; Proteins; Protocols documentation; Publications; Research; Resources; Rest; Risk Factors; Role; Scanning; Serum; Signal Transduction; Staging; Statistical Methods; Sterile coverings; Stratification; Study Subject; Testing; Validation; Variant; case control; cell type; cohort; cost; cytokine; dark matter; disease phenotype; endophenotype; evidence base; exome; exome sequencing; gene discovery; genetic linkage; genetic pedigree; genetic variant; genome wide association study; genome-wide; heart disease risk; identity by descent; interest; member; neglect; novel; novel diagnostics; operation; personalized medicine; public health relevance; rare variant; research study; segregation; simulation; tool; trait; wiki

DESCRIPTION (provided by applicant): Recent large scale GWAS, including ours in the NHLBI Family Heart Study (FamHS), have identified and validated many loci for heart disease phenotypes at GW levels of significance. Yet the importance of these loci remains uncertain as nearly all appear to explain minimal amounts of the variance for the traits studied. A number of large scale exome sequencing projects are now being conducted on case-control cohorts to ad- dress whether rare coding variants may be behind this "missing heritability". But so far, signals have been difficult to distinguish from noise, partly due to large number of evolutionarily recent variants found in human populations (e.g. Coventry et al., 2010). For such nearly private, lineage-specific mutations, unrelated case- control studies result in a large number of singleton variants with low individual power, and which collectively pose a challenge to burden testing. The recently developed exome-chip addresses part of this problem by focusing on the "not so rare" exonic variants (seen in multiple unrelated subjects), but neglects the evolutionary recent lineage-specific exonic variants which the Fisher-Wright model predicts would have the greatest penetrance effects. More importantly, the exclusive focus on exonic variation in both case-control sequencing and exome chip studies ignores regulatory variants, which may be most important to many of the quantitative endophenotypes of cardiovascular disease (e.g. serum lipids, cytokines, obesity, CAC). To address these research gaps, we propose using the large, well characterized family study, FamHS, as a platform for Whole Exome Sequencing (WES), plus Targeted Regulatory Sequencing (TRS) for variants associated with cardiovascular disease, atherosclerosis and associated endophenotypes. The FamHS represents the ideal resource for the proposed studies, having a unique combination of features which no other NHLBI cohort possesses. Results from GAW 17 show (Wilson and Ziegler, 2011), and our own simulations confirm, that family studies have greater power to detect near-private, lineage-specific rare variants than studies of unrelated subjects, allowing us greater ability to detect novel associated exonic variants than the current case- control WES and exome chip studies. Further, our FamHS pedigrees continue to show provocatively strong, independently replicated linkage evidence for a variety of cardiovascular traits, unexplained by GWAS SNPs, suggesting that these particular regions may contain rare coding and/or regulatory variants. We propose a two-stage, WES+TRS experiment on all N=5,763 European-Americans (EAs) (in 1,253 families) from the extensively phenotyped FamHS cohort. In Stage 1, we will obtain WES information for 3,389 FamHS EAs comprising the largest 491 pedigrees (mean family size=6.9), to scan for novel rare coding/regulatory variants for CHD, atherosclerosis, and their risk factor phenotypes, such as obesity, hypertension, dyslipidemia, diabetes, insulin resistance, and inflammation. In Stage 2, we will validate these regions by sequencing all implicated loci in the remaining independent FamHS subjects (N=2,374 EAs in 660 families). We will also validate these findings in the N=622 (F=221 families) African-Americans in FamHS by conducting parallel WES+TRS.

描述（由申请人提供）：最近的大规模GWA，包括我们在NHLBI家庭心脏研究（FAMHS）中的大型GWA，已确定并验证了许多在GW显着性水平的心脏病表型的基因座。然而，这些基因座的重要性仍然不确定，因为几乎所有人似乎都解释了所研究特征的差异的最小数量。现在，正在对病例对照组进行许多大规模的外显子组测序项目，以适应这种“缺失的遗传力”是否可能落后于稀有的编码变体。但是到目前为止，信号很难与噪声区分开，部分原因是在人类种群中发现了大量进化的变体（例如Coventry等，2010）。对于这种几乎私人的谱系特异性突变，无关的病例控制研究导致大量具有低个体功率的单例变体，并且对负担测试构成了挑战。最近开发的外部芯片通过关注“不那么罕见”的外显子变体（在多个无关的受试者中可见）来解决此问题的一部分，但忽略了Fisher-Wright模型预测的进化最近特定的外显子变体将具有最大的渗透效果。更重要的是，专有对病例对照测序和外部芯片研究的外部变化的专有忽略了调节变体，这对于许多心血管疾病的定量内跨表型可能最为重要（例如，血清脂质，细胞因子，肥胖，CAC，CAC）。 为了解决这些研究差距，我们建议使用大型的，具有良好特征的家庭研究，FAMHS作为整个外显子组测序（WES）的平台，以及针对与心血管疾病，动脉粥样硬化和相关内型型相关的变体的有针对性调节测序（TRS）。 FAMHS代表了拟议的研究的理想资源，具有独特的特征组合，而其他NHLBI队列没有任何功能。 GAW 17的结果表明（Wilson和Ziegler，2011年），我们自己的模拟证实，与无关的受试者的研究相比，家庭研究具有更大的能力来检测近乎私有的，谱系特定的稀有变体，从而使我们能够比当前的病例控制WES和Exome Contome WeS和Exome Chip研究更大的能力。此外，我们的Famhs谱系继续显示出挑衅性的强大，独立复制的连锁证据，证明了各种心血管特征，无法解释GWAS SNP，这表明这些特定地区可能包含罕见的编码和/或监管变体。我们从广泛表型的FAMHS队列中提出了所有n = 5,763个欧洲裔美国人（EAS）（EAS）（EAS）（EAS）（EAS）（EAS）（EAS）的两个阶段，WES+TRS实验。在第1阶段，我们将获得3,389个FAMHS EA的WES信息，其中包括491个谱系（平均家庭尺寸= 6.9），以扫描有关CHD，动脉粥样硬化，动脉粥样硬化及其风险因素表型的新型稀有编码/调节变体，例如肥胖，肥胖，高血压，低血压，耐症状，疾病，疾病，疾病，及耐抑制性。在第2阶段中，我们将通过对所有涉及的基因座进行测序来验证这些区域（660个家庭中的n = 2,374 EAS）。我们还将通过进行平行的WES+TRS中的N = 622（F = 221个家庭）非裔美国人的n = 622（F = 221个家庭）中验证这些发现。