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

描述（由申请人提供）：纤维化间质性肺病（Fibrosing interstial lung disease, field）是指一组因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可以可靠地缓解症状或延长寿命。field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，其中大多数是未知的。这个项目的动机是我们正在完成的两项大型field全基因组研究：一项家族连锁研究和一项病例对照关联研究。我们将对家族性研究中的病例以及其他病例和对照进行测序，以确定这些研究中高优先区域内的风险位点。测序研究将优先考虑罕见（<1%）和不常见（<5%）的变异。在病例对照设置中，已经开发了几种罕见和不常见变异的关联测试，其中变异被汇总以提高统计能力。然而，这些统计测试都没有使用家族特异性连锁信息，这些信息对遗传异质性具有很高的信息性。因此，目前还没有将特定家族的连锁信息整合到关联的综合检验中的方法。的目标

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.