Studies of Rare Genetic Variation in the Isolated Population of Sardinia

描述(申请人提供)：下一代测序正在逐渐改变人类基因研究的面貌。全基因组研究不再局限于对许多群体共有的常见SNPs的分析，并适用于微阵列基因分型，而是现在可以研究更广泛的遗传变异--包括更多样化的变异类型(如插入-缺失多态)、特定样本或群体特有的变异以及罕见和低频率的变异。在此，我们请求继续支持我们对意大利撒丁岛与世隔绝的人群中与衰老相关的特征的遗传分析，重点是心血管风险因素。在接下来的几年里，我们将使用下一代测序技术和高通量基因分型技术，在一个包含约6,000个个体(和30,000个近亲配对)的家庭样本中研究罕见的基因变异与关键心血管风险因素之间的关系。作为我们计划的实验的一部分，我们将评估与测序样本的选择、测序实验和方案的设计、结果序列数据的分析和管理，以及将产生的变异与相关生物医学特征联系起来的关联分析相关的问题。被研究的个体是对衰老的纵向研究的一部分，并已被描述为心血管特征和结果，包括对关键特征的多项测量，如血脂水平和血压。我们之前已经对这个样本进行了研究，以确定与这些心血管特征相关的常见基因变异，这些变异也会导致心脏病和肥胖的风险。我们提出的实验计划提供了一个独特的机会来评估罕见变异在这个独特样本中的作用。我们希望这些研究将产生实验策略和分析工具，许多实验室可以随时部署这些策略和分析工具来研究许多其他个体的基因组，并进一步了解许多不同特征和条件的遗传学和生物学。

DESCRIPTION (provided by applicant): Next generation sequencing is gradually changing the face of human genetic studies. Instead of being largely confined to the analysis of common SNPs shared across many populations and amenable to microarray genotyping, genome-wide studies can now examine a wider range of genetic variants - including more diverse types of variation (such as insertion-deletion polymorphisms), variants specific to particular samples or populations, and rare and low frequency variants. Here, we request continued support for our genetic analysis of aging related traits - with a focus on cardiovascular risk factors - in the isolated population from the island of Sardinia, Italy. Over the next several years, we will use next-generation sequencing technology and high-throughput genotyping to study the relationship between rare genetic variation and key cardiovascular risk factors in a family sample containing ~6,000 individuals (and >30,000 close relative pairs) recruited in the Lanusei valley. As part of our planned experiments, we will evaluate problems related to the selection of samples for sequencing, the design of sequencing experiments and protocols, the analysis and curation of the resulting sequence data, and - finally - association analyses that connect the resulting variants to relevant biomedical traits. Individuals being studies are part of a longitudial study of aging and have been characterized for cardiovascular traits and outcomes, including multiple measurements of key traits such as blood lipid levels and blood pressure. We have previously studied this sample to identify common genetic variants that are associated with these cardiovascular traits and that also contribute to the risk of heart disease and obesity. Our proposed experimental plan presents a unique opportunity to evaluate the role of rare variation in this unique sample. We expect that these studies will result in experimental strategies and analysis tools that will be readily deployable by many laboratories to study the genomes of many other individuals and further our understanding of the genetics and biology of many different traits and conditions.