Whole Genome Sequence Imputation in Families for Echocardioagraphic Traits

7.摘要 全基因组关联研究（GWAS）在过去的5-10年中取得了巨大的成功， 确定广泛的心血管疾病及其危险因素的常见遗传变异。然而 与这些特征相关的大部分遗传变异仍然无法解释，这表明仍然有一些遗传变异。 许多未被发现的遗传变异被发现。各种各样的解释已经被假设来解释 这种未知遗传变异的来源，包括基因×环境互作、基因×基因互作 以及具有较小影响的附加常见变体。一个重要的潜在来源， 变异可能是不太常见或罕见的变异。为了追踪这些变异，靶向和外显子组测序 过去数年已进行研究。这些研究的目标是充分描述所有 目标区域或外显子区域的遗传变异及其与疾病特征和风险因素的关联。整个 基因组测序在获得基因组中遗传变异的完整描述方面可能更有成效 并且在定位GWAS的致病变体方面确实可能比外显子组测序更成功 通常在蛋白质编码区之外的信号。家庭研究可能提供一个有效的设计 为了评估这些变异，由于家族中罕见变异的频率（这些变异被传递的地方）， 下一代）的频率远远大于一般人群中该变异的频率。 此外，家系研究提供了一个重要的结构，可以更准确地估算罕见变异， 在相同大小的不相关个体的群体中， 需要排序。因此，我们提出以下目标：目标1：利用现有的GWA、外显子组芯片和 心脏病研究家庭参与者的一个子集中的全基因组测序基因型， 在其余具有GWA和外显子组芯片基因型的家族成员中的全基因组序列变异。我们将 检查在此估算中使用外显子组芯片变体的附加值。我们将探讨几种方法 用于插补，以确定哪种方法提供了插补基因型的最佳插补质量。 此外，我们还将检查是否有其他参考骨干用于FractionalStudy之外的插补。 提供比具有所有三种类型遗传变异的Fragrance中的个体更好的插补质量（WGS， 目的2：使用最佳质量的估算全基因组序列变异 在目标1中获得，以检查不常见和罕见变异与超声心动图之间的相关性。 性状这项研究为在美国进行全基因组测序研究提供了基础。 心脏病研究和协作家庭研究。

7. Abstract Genome-wide association studies (GWAS) have been enormously successful over the past 5-10 years in identifying common genetic variants for a wide range of cardiovascular diseases and their risk factors. Yet much of the genetic variation associated with these traits remains unexplained, suggesting that there are still many undiscovered genetic variants to be found. A variety of explanations have been posited to explain the source of this unidentified genetic variation, including gene x environment interaction, gene x gene interaction and additional common variants with smaller effects. One important potential source of this unidentified variation may be less common or rare variants. To pursue such variants, targeted and exome sequencing studies have been conducted over the past few years. The goal of these studies was to fully delineate all genetic variation in targeted or exonic regions and its association with disease traits and risk factors. Whole genome sequencing may be more fruitful in obtaining a full delineation of the genetic variation in the genome and may indeed provide greater success than exome sequencing in locating the causal variants for GWAS signals that are frequently outside protein coding regions. A family study is likely to provide an efficient design to evaluate such variants, since the frequency of a rare variant in families (where these variants are passed down the generations) is substantially larger than the frequency of that variant in the general population. Furthermore, family studies provide an important structure to impute rare variation much more accurately than in populations of unrelated individuals of the same size, thereby saving sequencing costs as fewer individuals need to be sequenced. Thus, we propose the following aims: Aim 1: To use existing GWA, exome chip and whole genome sequencing genotypes in a subset of Framingham Heart Study family participants to impute whole genome sequence variants in remaining family members with GWA and exome chip genotypes. We will examine the added value of using exome chip variants in this imputation. We will explore several approaches for imputation to determine which approach provides the best imputation quality of imputed genotypes. Additionally, we will examine whether other reference backbones for imputation outside the Framingham Study provide better imputation quality than individuals in Framingham with all three types of genetic variants (WGS, exome chip and GWA); and Aim 2: To use the best quality imputed whole genome sequence variation obtained in Aim 1 to examine the associations between less common and rare variants with echocardiographic traits. This research provides the foundation for pursuing whole genome sequencing studies in the Framingham Heart Study and in collaborating family studies.