FHS-Molecular Genetics & Genetic Epidemiology

描述（研究者摘要）：本次更新的主要目标 NHLBI家庭心脏研究（FHS）研究者的申请是 鉴定与CHD、动脉粥样硬化性心脏病（atherosclerotic heart disease，AS） 通过超声测量的负担及其危险因素。第二个目标是 表征冠心病危险因素的相互作用和遗传流行病学， 所识别的基因组区域的术语。最近完成的全基因组 扫描，进行大FHS样本的扩展谱系，将允许 在10%-15%（位点特异性）遗传率范围内检测基因。 第三个目标是做一个有限的，集中的数量更密集的基因分型的标记 在最有希望的地区，验证结果，并开始更多的 精确地定义峰值。最先进的分析方法和软件将 利用互补的遗传流行病学专门知识， 在FHS的五个地点组装，科学，分析和数据 FHS协调中心的管理支持。这些计划是尖锐的 专注于完成基因组扫描的分析和出版。小说 遗传分析方法将用于解决表型， 遗传和群体异质性，上位性， 遗传和环境风险因素，并优化检测 影响CHD易感性和危险因素的基因组区域。的 基因组扫描中臭名昭著的多重比较问题将被绕过 同时使用新的全局测试程序。在此前的一次 FHS的资金周期，我们广泛地描述了CHD和相关的 随机抽取583个家系，649个冠心病家系， （CHD）易感家系和59个非洲裔美国人家系（5，818人） 从四个流行病学定义的人群中抽取， 优质DNA这些表型数据的分析和出版是积极的 在对选定的候选基因进行基因分型的同时， 在1,184个高风险兄弟姐妹上的244个犹他州标记的粗略地图。尽管未 最初预计，现在可获得404个标记的额外密集地图 来自哺乳动物基因分型服务的3，027名个体来自401个最大的 扩展FHS谱系。目前的资金已于2000年7月到期， 分析这个意想不到的基因分型，现在已经完成了对 大多数最大和最翔实的FHS谱系。这一延长将 使这一独特的资源可用于确定基因组区域， 来自所有主要风险因素领域的各种CHD相关特征。

DESCRIPTION (Investigator's abstract): The primary goal of this renewal application from the NHLBI Family Heart Study (FHS) investigators is to identify the genomic regions linked and/or associated with CHD, atherosclerotic burden measured by ultrasound, and their risk factors. A secondary aim is to characterize interactions and the genetic epidemiology of CHD risk factors in terms of the identified genomic regions. The recently completed genome-wide scan, conducted upon large FHS samples of extended pedigrees, will allow detection of genes in the range of 10-15 percent (locus-specific) heritability. A third aim is to do a limited, focused amount of denser genotyping of markers in the most promising regions, to verify the results and begin to more precisely define the peaks. State of the art analytic methods and software will be applied, drawing on the complementary genetic epidemiology expertise assembled at five sites of the FHS, with scientific, analytic, and data management support from the FHS Coordinating Center. The plans are sharply focused on completing the analysis and publication of the genome scans. Novel genetic analysis methods will be used to address the issues of phenotypic, genetic and population heterogeneity, epistasis, complex interactions among the genetic and environmental risk factors, and to optimize the detection of genomic regions affecting CHD susceptibility and the risk factors. The notorious issue of multiple comparisons in genome scans will be bypassed altogether with the use of novel global testing procedures. During a previous funding cycle of the FHS, we extensively characterized the CHD and associated traits in subjects from 583 random sample pedigrees, 649 coronary heart disease (CHD)-prone pedigrees, and 59 African-American pedigrees (5,818 individuals) drawn from four epidenuologically defined populations, with banking of high quality DNA. Analysis and publication of these phenotypic data was actively pursued while genotyping was underway for selected candidate genes as well as for a coarse map of 244 Utah markers on 1,184 high risk siblings. Although not originally anticipated, an additional dense map of 404 markers is now available from the Mammalian Genotyping Service on 3,027 individuals from the 401 largest extended FHS pedigrees. Current funding expired in July 2000, too late to analyze this unanticipated genotyping that has now been completed on the majority of the largest and most informative FHS pedigrees. This extension will make this unique resource available for identifying genomic regions influencing a wide variety of CHD associated traits from all major risk factor domains.