Integrating linkage information in tests of association for rare variants in ILD

将连锁信息整合到 ILD 罕见变异的关联测试中

• 批准号: 8994052
• 负责人: Tasha E. Fingerlin
• 金额: $ 16.59万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8994052
• 关键词: Integrating; linkage; information; tests; association

DESCRIPTION (provided by applicant): Fibrosing interstitial lung disease (fILD) refers to a group of lung diseases that result in significant morbidity and mortality due to progressive scarring of the alveolar interstitium. There are no effective treatments to reliably relieve symptoms or prolong life. FILD is a complex disease likely caused by the interplay among multiple genetic and environmental factors, most of which are unknown. This project is motivated by two large genome-wide studies of fILD that we are completing: one familial linkage study and one case-control association study. We will sequence cases from the familial study in addition to other cases and controls to identify the risk loci within the high priority regions fro these studies. A priority for the sequencing study will be rare (<1%) and uncommon (<5%) variants. Several tests of association for rare and uncommon variants have been developed in the case-control setting, where the variants are aggregated to improve statistical power. However, none of these statistical tests use family-specific linkage information, information that is highly informative for genetic heterogeneity. Hence, there are no existing methods for integration of family-specific linkage information into aggregate tests of association. The goal of this project is to fill this gap in statistical methodology for directly combining family-specific linkage information with other case-control sequence data in order to identify genetic risk variants for fILD. The central hypothesis of this project is that the power of genetic association tests for rare variants can be improved by using family-specific allele sharing information to give more weight to familial cases from families with evidence for linkage at the locus of interest. We propose extensions of rare/uncommon variant tests of association that a) require only one case per family, b) use external measures of allele sharing from linkage studies, and c) allow joint analysis of familial cases with linkage information and other cases. The first aim is to evaluate a new framework for weighted tests of association between a group of rare/uncommon genetic variants and a dichotomous trait. The contribution of each familial case is weighted according to the case's family-specific evidence for allele sharing at the locus of interest. The second aim is to apply the new methods to fILD to identify novel variants that increase the risk of fILD and compare the results to those obtained using existing methods. The third aim is to develop and disseminate a freely-available implementation of the tests developed in aim 1, which will facilitate the application of these methods to other disorders. While two studies of fILD motivate this work, there are hundreds of similar studies with available linkage data which would benefit from the increased power to detect risk variants with these tests. The successful completion of this science will result in tests of association and software applicable to resequencing studies that improve power by leveraging the information contained in, and the resources that have been devoted to, familial linkage cohorts. The methods are naturally extendable to quantitative traits and other complex testing strategies to increase power to detect functional variants.

描述(申请人提供)：纤维性间质性肺疾病(FIRD)是指一组由于肺泡间质进行性瘢痕形成而导致显著发病率和死亡率的肺部疾病。目前还没有有效的治疗方法来可靠地缓解症状或延长生命。FILD是一种复杂的疾病，可能是由多种遗传和环境因素相互作用引起的，其中大多数因素尚不清楚。该项目是由我们正在完成的两项大型全基因组FIRD研究推动的：一项家族性连锁研究和一项病例对照关联研究。除了其他病例和对照外，我们还将对家族性研究中的病例进行排序，以确定这些研究的高优先级区域内的风险基因。测序研究的重点将是罕见(1%)和不常见(5%)的变异。在病例对照的情况下，对罕见和不常见的变异进行了几项关联测试，这些变异被聚集在一起以提高统计能力。然而，这些统计检验都没有使用特定于家族的连锁信息，这些信息对遗传异质性具有很高的信息量。因此，没有现有的方法将特定于家庭的连锁信息整合到关联的聚合测试中。的目标是 该项目旨在填补统计方法上的这一空白，直接将特定于家庭的连锁信息与其他病例对照序列数据相结合，以确定FIRD的遗传风险变异。该项目的中心假设是，通过使用特定于家族的等位基因共享信息来提高对罕见变异的遗传关联测试的能力，可以给出 更重视有兴趣基因连锁证据的家庭的家族性病例。我们建议扩展罕见/不常见的关联变异检验，a)每个家庭只需要一个病例，b)使用来自连锁研究的等位基因共享的外部测量，以及c)允许对具有连锁信息的家族性病例和其他病例进行联合分析。第一个目标是评估一个 加权检验一组罕见/不常见的基因变异和一个二分性状之间的关联性的新框架。每个家族性病例的贡献是根据病例在感兴趣基因座共享等位基因的特定家族证据来加权的。第二个目标是将新方法应用于FIRD，以确定增加FIRD风险的新变种，并将结果与使用现有方法获得的结果进行比较。第三个目标是开发和传播目标1中开发的测试的免费实施，这将促进将这些方法应用于其他障碍。虽然FIRD的两项研究推动了这项工作，但有数百项类似的研究使用了可用的关联数据，这些研究将受益于通过这些测试检测风险变异的更大能力。这项科学的成功完成将导致对关联性和适用于重新排序研究的软件进行测试，这些研究通过利用家族连锁队列中包含的信息和已投入的资源来提高能力。这些方法自然可以扩展到数量性状和其他复杂的测试策略，以增加检测功能变异的能力。