Whole Genome Sequence Imputation in Families for Echocardioagraphic Traits

描述（由申请人提供）：全基因组关联研究（GWAS）在过去5-10年中在确定广泛心血管疾病及其风险因素的常见遗传变异方面取得了巨大成功。然而，与这些性状相关的遗传变异仍然无法解释，这表明仍有许多未被发现的遗传变异有待发现。各种解释已经被假定来解释这些未被发现的遗传变异的来源，包括基因x环境互作，基因x基因互作和其他影响较小的常见变异。这种未识别变异的一个重要潜在来源可能是不太常见或罕见的变异。为了追踪这些变异，在过去几年中进行了靶向和外显子组测序研究。这些研究的目的是充分描绘靶向或外显子区域的所有遗传变异及其与疾病特征和风险因素的关联。全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，并且在定位经常在蛋白质编码区之外的GWAS信号的致病变体方面确实可能比外显子组测序提供更大的成功。家族研究可能提供一种有效的设计来评估这些变异，因为家族中罕见变异的频率（这些变异在家族中代代相传）远远大于一般人群中该变异的频率。此外，家庭研究提供了一个重要的结构，比在相同大小的无关个体的群体中更准确地估算罕见变异，从而节省测序成本，因为需要测序的个体更少。因此，我们提出了以下目标：目标1：使用现有的GWA，外显子组芯片和全基因组测序基因型在一个子集的心脏研究的家庭参与者的全基因组序列变异的其余家庭成员与GWA和外显子组芯片基因型。我们将研究在这种插补中使用外显子组芯片变体的附加值。我们将探讨几种插补方法，以确定哪种方法提供了插补基因型的最佳插补质量。此外，我们将检查Frachial研究之外的其他参比骨干是否比Frachial中具有所有三种类型遗传变异（WGS，外显子组芯片和GWA）的个体提供更好的插补质量;目的2：使用目的1中获得的最佳质量插补全基因组序列变异来检查不太常见和罕见变异与超声心动图特征之间的关联。这项研究为在Frachial Heart研究和合作家庭研究中进行全基因组测序研究提供了基础。

DESCRIPTION (provided by applicant): 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.