Studies of Rare Genetic Variation in the Isolated Population of Sardinia

描述（由申请人提供）：下一代测序正在逐渐改变人类遗传学研究的面貌。全基因组研究不再局限于分析许多人群中共有的常见SNP，而是可以检测更广泛的遗传变异-包括更多样化的变异类型（如插入-缺失多态性），特定样本或人群的特异性变异，以及罕见和低频率变异。在此，我们请求继续支持我们对来自意大利撒丁岛的孤立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来研究在Lanusei山谷招募的包含约6，000个个体（和> 30，000个近亲对）的家庭样本中罕见遗传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品的选择、测序实验和方案的设计、所得序列数据的分析和管理以及最后将所得变体与相关生物医学性状联系起来的关联分析相关的问题。被研究的个体是衰老的一项临床研究的一部分，并已被表征为心血管特征和结果，包括对血脂水平和血压等关键特征的多项测量。我们以前研究过这个样本，以确定与这些心血管特征相关的常见遗传变异，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，以评估在这个独特的样本中罕见的变化的作用。我们期望这些研究将产生实验策略和分析工具，这些工具将易于被许多实验室部署，以研究许多其他个体的基因组，并进一步了解许多不同性状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.