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（由申请人提供）：纤维间肺肺疾病（FILD）是指由于肺泡间质的逐渐疤痕，导致一组肺部疾病导致显着发病和死亡。没有有效的治疗方法可靠地缓解症状或延长寿命。 FILD是一种复杂的疾病，可能是由于多个遗传和环境因素之间的相互作用引起的，其中大多数是未知的。该项目是由我们正在完成的两项大型基因组研究的动机：一项家族联系研究和一项病例对照协会研究。除其他病例和对照外，我们还将对家族研究的病例进行序列，以确定这些研究的高优先级区域内的风险基因座。测序研究的优先级将很少见（<1％）和罕见（<5％）变体。在病例对照的环境中已经开发了几种稀有和不常见变体的关联测试，其中汇总了变体以提高统计能力。但是，这些统计检验均未使用家庭特定的链接信息，这些信息对于遗传异质性提供了极大的信息。因此，没有将特定于家庭的链接信息整合到关联汇总测试中的现有方法。目标 该项目是在统计方法中填补这一空白，以将家族特异性链接信息与其他病例对照序列数据直接相结合，以确定FILD的遗传风险变异。该项目的核心假设是，可以通过使用家庭特定的等位基因共享信息来改善稀有变体的遗传关联测试的力量 家庭病例的重量更大，有证据可以在感兴趣的基因范围内进行联系。我们提出了稀有/不常见变体的关联测试的扩展，a）a）每个家庭只需要一个案例，b）使用链接研究中的等位基因共享的外部测量，c）允许对家庭案例进行联合分析与链接信息和其他案例。第一个目的是评估 一组稀有/不常见的遗传变异和二分法性状之间关联的加权测试的新框架。每个家族案例的贡献是根据该案的家庭特定证据加权等位基因在感兴趣的位置共享的。第二个目的是应用新方法来识别新的变种，以增加fild的风险，并将结果与​​使用现有方法获得的结果进行比较。第三个目的是开发和传播AIM 1中开发的测试的自由实施，这将有助于将这些方法应用于其他疾病。虽然两项关于fild的研究激发了这项工作，但有数百种类似的研究和可用的连锁数据，这些研究将受益于通过这些测试来检测风险变异的功率的增加。该科学的成功完成将导致对关联和软件的测试，适用于重新陈述研究，从而通过利用所包含的信息以及专门用于家族链接队列的资源来改善功率。这些方法自然可扩展到定量性状和其他复杂的测试策略，以增加检测功能变体的功率。