Family Linkage Study of Obstructive Sleep Apnea

产品说明：（申请人提供）阻塞性睡眠呼吸暂停（OSA）存在家族聚集性，如在美国、欧洲和最近在冰岛所示。冰岛为基因研究提供了一个独特的机会。它是一个由创始人在世纪定居的社区，从那时起在相对孤立的情况下发展到现在的285，000人的规模。 此外，有一个承诺，以记录保存，已允许解码遗传学，谁是合作者，在这个赠款，开发一个计算机化的家谱数据库，允许个人的祖先追溯了几个世纪。这个工具，加上人口的创始人性质，使得一个独特的系谱驱动的方法来研究复杂疾病的遗传学成为可能，这种方法已经取得了成功。我们建议在这个应用程序中研究的遗传基础的常见疾病-阻塞性睡眠呼吸暂停--使用这种系谱的方法。这项研究将建立在患有这种疾病的患者身上，这些患者已经在冰岛被诊断出来，并且已经确定了大家族谱系。这项研究涉及全基因组的家庭连锁调查。 这将采用仅受影响的方法进行，使用分布在基因组中的1，100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采样，为我们提供机会来评估相对非肥胖和肥胖受试者之间的联系。关联研究将与关联研究相补充，关联研究包括不相关的病例和对照，年龄、性别和绝经状态相匹配。在关联研究中，我们的主要目的是检测连锁研究中产生的候选基因，其次是评估我们认为将在正在进行的克利夫兰家族研究中确定的候选基因。在家族连锁和关联研究中的一个受试者子集将进行深入的表型分析，以确定这种复杂疾病是否存在亚表型，如果存在，它们是否在家族中聚集。这种深入的表型分析将涉及上气道磁共振成像，以评估上气道软组织和颅面结构，声学阻抗测量，以量化鼻阻力，一个已知的疾病的危险因素，和胰岛素抵抗。我们将探讨是否有不同的连锁模式的不同亚表型。为了完成这项大型遗传研究，我们汇集了三个主要组织的资源-宾夕法尼亚大学，冰岛大学医院和解码遗传学。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计划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.