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: 8874275
• 负责人: Michael A. Province
• 金额: $ 74.07万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8874275
• 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; targeted sequencing; 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GWAS，包括我们在NHLBI家族心脏研究（FamHS）中的研究，已经在GW水平上识别并验证了许多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，因为几乎所有基因座似乎都解释了所研究性状的最小方差。许多大规模的外显子组测序项目目前正在病例对照队列中进行，以确定这种“缺失的遗传性”背后是否存在罕见的编码变异。但到目前为止，信号很难从噪音中区分出来，部分原因是在人类群体中发现了大量进化上最近的变异（例如Coventry等人，2010）。对于这些几乎是私人的、谱系特异性的突变，不相关的病例对照研究导致大量个体功率低的单例变异，这对负担测试构成了挑战。最近开发的外显子芯片通过关注“不那么罕见”的外显子变体（在多个不相关的对象中看到）来解决部分问题，但忽略了进化最近的谱系特异性外显子变体，Fisher-Wright模型预测这些外显子变体将具有最大的外显子效应。更重要的是，病例对照测序和外显子组芯片研究都只关注外显子变异，而忽视了调控变异，而调控变异可能对许多心血管疾病的定量内表型（如血脂、细胞因子、肥胖、CAC）最为重要。为了解决这些研究空白，我们建议使用大型的、具有良好特征的家族研究FamHS作为全外显子组测序（WES）的平台，以及与心血管疾病、动脉粥样硬化和相关内表型相关的变异的靶向调节测序（TRS）。FamHS代表了拟议研究的理想资源，具有其他NHLBI队列所不具备的独特特征组合。GAW 17的结果表明（Wilson和Ziegler， 2011），我们自己的模拟也证实，与不相关的研究相比，家族研究在检测近私有的、谱系特异性的罕见变异方面具有更大的能力，这使我们能够比目前的病例对照WES和外显子组芯片研究更能检测到新的相关外显子变异。此外，我们的FamHS谱系继续显示出令人不安的强大的、独立复制的连锁证据，表明这些特定区域可能包含罕见的编码和/或调节变异，这些证据与各种心血管特征有关，无法用GWAS snp解释。我们对来自广泛表型的FamHS队列的所有N= 5763名欧美人（1253个家庭）进行了两阶段WES+TRS实验。在第一阶段，我们将获得3389个FamHS ea的WES信息，包括最大的491个家系（平均家庭规模=6.9），以扫描冠心病、动脉粥样硬化及其危险因素表型（如肥胖、高血压、血脂异常、糖尿病、胰岛素抵抗和炎症）的新型罕见编码/调节变异。在第二阶段，我们将通过对其余独立FamHS受试者（660个家族的2374个ea）中所有涉及的基因座进行测序来验证这些区域。我们还将通过平行WES+TRS在FamHS的N=622 （F=221个家庭）非裔美国人中验证这些发现。