Family Linkage Study of Obstructive Sleep Apnea

描述：(申请人提供)阻塞性睡眠呼吸暂停(OSA)的家庭聚集性，如美国、欧洲和最近在冰岛所显示的。冰岛代表着一个独特的基因研究机会。这是一个由创始人在9世纪建立的社区，自那时以来一直在相对孤立的情况下发展到现在的285,000人的规模。此外，对记录保存的承诺使deCODE Genetics得以开发一个计算机化的家谱数据库，使其能够追溯几个世纪以来的个人祖先。这一工具与人群的创建者性质一起，使一种独特的家谱驱动的方法成为可能，以研究复杂疾病的遗传学，这种方法已经取得了成功。在这项应用中，我们建议使用这种系谱方法来研究常见疾病-阻塞性睡眠呼吸暂停的遗传基础。这项研究将建立在患有这种疾病的患者的基础上，这些患者已经在冰岛被诊断出患有这种疾病，并在那里被确定了大家族谱系。这项拟议的研究涉及一项全基因组的家庭连锁调查。这将通过一种仅受影响的方法来进行，使用分布在基因组中的1100个标记来检查受影响个体之间的等位基因共享。我们计划对相对非肥胖的受试者进行过度抽样，为我们提供评估相对非肥胖者和肥胖者之间的联系的机会。该关联研究将与关联研究相辅相成，包括年龄、性别和绝经状态相匹配的无关病例和对照。在关联研究中，我们将作为主要目标，测试来自连锁研究的候选基因，并作为次要目标，评估我们认为将在正在进行的克利夫兰家庭研究中确定的候选基因。在家族连锁和关联研究中，受试者的一个子集将进行深入的表型分析，以确定这种复杂疾病是否有亚型，如果有，它们是否聚集在家族中。这一深入的表型将涉及上呼吸道磁共振成像以评估上呼吸道软组织和颅面结构，声学鼻腔测量以量化鼻阻力，鼻阻力是该疾病的已知危险因素，以及胰岛素抵抗。我们将探索不同的亚型是否有不同的连锁模式。为了完成这项大规模的基因研究，我们汇集了三个主要组织的资源--宾夕法尼亚大学、冰岛大学医院和DeCODE Genetics。我们建议利用deCODE Genetics开发的真正独特的基础设施、冰岛大学医院的睡眠呼吸暂停临床研究项目以及宾夕法尼亚大学的深入表型专业知识来实现我们的目标。

DESCRIPTION: (provided by applicant) There is family aggregation of obstructive sleep apnea (OSA) as has been shown in the United States, Europe and recently in Iceland. Iceland represents a unique opportunity for genetic research. It is a community that was settled by founders in the 9 th Century, and has developed in relative isolation since that time to its present size of 285,000 persons. Moreover, there is a commitment to record keeping that has allowed deCODE Genetics, who are collaborators on this grant, to develop a computerized genealogy data base that permits the ancestry of individuals to be traced over centuries. This tool, together with the founder nature of the population, makes possible a unique genealogy-driven approach to study the genetics of complex disorders, an approach that has already been successful. We propose in this application to study the genetic basis of the common disorder---obstructive sleep apnea--using this genealogical approach. The study will be built on patients with the disorder, who have already been diagnosed in Iceland and where large family pedigrees have been identified. The proposed study involves a genome-wide family linkage investigation. This will be conducted with an affected only approach examining allele sharing between affected individuals using 1,100 markers spaced across the genome. We plan to oversample the relatively non-obese subjects providing us the opportunity to evaluate linkage in both relatively non-obese and obese subjects. The linkage study will be complemented with an association study, with unrelated cases and controls, matched for age, gender, and menopausal status. In the association study, we will, as a primary aim, test candidate genes arising from the linkage study and, as a secondary aim, evaluate candidate genes that we believe will be identified in the ongoing Cleveland Family Study. A subset of subjects in both the family linkage and association study, will have in-depth phenotyping to determine whether there are sub-phenotypes for this complex disorder and, if so, whether they aggregate in families. This in depth phenotyping will involve upper airway magnetic resonance imaging to evaluate upper airway soft tissue and craniofacial structures, acoustic rhinometry to quantify nasal resistance, a known risk factor for the disorder, and insulin resistance. We will explore whether there are distinct patterns of linkage for the different sub-phenotypes. To accomplish this large genetic study, we have put together the resources of three major organizations--the University of Pennsylvania, the University of Iceland Hospitals, and deCODE Genetics. We propose to leverage the truly unique infrastructure developed by deCODE Genetics, the clinical research programs in sleep apnea at the University of Iceland Hospitals, and the in-depth phenotyping expertise at the University of Pennsylvania to accomplish our goals.