A Biologically Informed Method for Detecting Associations with Rare Variants

描述(由申请人提供)：全基因组关联研究在识别与表型差异相关的常见变异方面取得了一定的成功。然而，在任何给定的复杂性状中，可遗传成分的大部分尚未得到解释。允许表征稀有变异、结构变异和表达数据的新技术正在为性状关联提供新的见解。不幸的是，数据的创建速度快于现场分析的速度。目前的通用变种分析方法不能管理序列数据；因此，有必要设计新的方法来管理高通量数据。这些新方法还应该能够分析相互作用(上位性和基因-环境)，并准备在其他“经济学”数据日益可用时纳入这些数据。单一方法完成这些复杂任务的能力将使研究人员能够描绘出包含多种形式的遗传和环境信息的特征的完整图景。由于环境是为数不多的可修改变量之一，因此确定基因-环境相互作用具有特别重要的意义。开发这种分析工具的一种方法是在两步分析中使用已知的生物信息。第一步使用基于知识的生物学和预测函数作为指导，将稀有变体折叠到加权垃圾箱中。这对于减少序列数据的计算负荷以及增加检测稀有变体之间的关联的能力是必要的。然后，可以立即(退出这条管道)测试绑定的变种和常见的变种，或者将其打包用于生物过滤器。在第二步中，生物过滤器创建和评估潜在的相互作用(基因-基因或基因-环境)。然后，这些相互作用模型在全基因组数据中进行测试，以寻找具有统计学意义的关联。在这两个步骤中，生物信息是从多个基因分组和疾病相关基因集合的公共数据库的系统集成中获得的，以产生具有既定生物学基础的多SNP模型。合并先验知识的优点是：减少了搜索空间，增加了识别关联的能力，并对任何统计上有意义的结果进行了相关生物学的推断。这个项目的第一个目标是开发BioBn，这是一种使用领域知识来指导稀有变体的折叠和打包的算法。第二个目标是使用模拟数据将该方法与其他已发表的折叠方法进行比较。第三个目标是建立一个管道，让生物过滤器对数据进行折叠和评估，特别是在与年龄相关的黄斑变性研究中使用个体来测试基因与环境的相互作用。

DESCRIPTION (provided by applicant): Genome-wide association studies (GWAS) have been moderately successful in identifying common variants that are associated with phenotypic differences. However, the greater part of the heritable component in any given complex trait has yet to be explained. New technologies which allow for the characterization of rare variants, structural variants, and expression data are providing new insights into trait association. Unfortunately, the data is being created faster than the field is able to analyze it. Current common-variant analytical methods are not powered to manage sequence data; therefore, new methods designed to manage high-throughput data are necessary. These new methods should also be capable of analyzing interactions (epistasis and gene-environment) and prepared to incorporate other "-omic" data as it increasingly becomes available. A single method's ability to perform these complex tasks will enable the researcher to paint a complete picture of a trait that incorporates many forms of genetic and environmental information. Identifying gene-environment interactions are of particular importance since environment is one of few modifiable variables. One approach for developing this analytical tool is to use known biological information in a two step-analysis. The first step uses knowledge-based biology and predicted function as guides to collapse rare variants into weighted bins. This is necessary to decrease the computational load of sequence data, as well as increase the power of detecting an association among rare variants. The binned variants along with common variants can then be tested for association immediately (exit this pipeline) or be packaged for Biofilter. In the second step, Biofilter creates and assesses potential interactions (gene-gene or gene-environment). These interaction models are then tested in genome-wide data for statistically significant association. In both steps, the biological information is derived from a systematic integration multiple public databases of gene groupings and sets of disease-related genes to produce multi-SNP models that have an established biological foundation. The advantages of incorporating prior knowledge are: reduced search space, increased power to identify associations, and inference of relevant biology for any statistically significant result. The first goal of this project is to develop BioBn, an algorithm that will use domain-knowledge to guide the collapsing and binning of rare variants. The second goal is to compare this method to other published collapsing methods using simulated data. The third goal is to create a pipeline for data to be collapsed and evaluated by Biofilter, specifically to test for gene-environment interactions using individuals in an Age-relatd Macular Degeneration study.