IDENTIFICATION OF GENES PREDISPOSING TO PELVIC FLOOR DISORDERS

描述(由申请人提供)：研究人员提议在犹他州的基础和临床科学家之间进行独特而强大的合作，以确定影响盆腔器官脱垂(POP)易感性的基因。这两位合作PI都有丰富的经验，诺顿博士在盆底疾病(PFD)遗传学方面，坎农-奥尔布赖特博士在易感基因识别方面。调查人员将访问犹他州人口数据库，这是犹他州的计算机化家谱，结合犹他州两个最大的医疗系统(服务于该州90%的地区)数十年的医疗数据，以识别和招募手术治疗的POP病例(5年内有1250例)。所有抽样的POP病例将使用Illumina 610Q SNP标记集进行基因分型。调查人员将对这一来源的POP病例进行多种不同的基因分析，以帮助识别易感基因。医疗程序代码(确定对每个患者进行的手术)与个人家谱数据的记录联系使我们能够识别POP病例之间的所有遗传关系。我们将使用我们开发的软件进行全基因组关联分析，该软件允许包括独立和相关的病例。我们将确定抽样流行病例之间的所有遗传关系，并在信息丰富的高危流行家系中进行连锁分析。我们将在这些家系中的非常遥远的亲缘关系的病例中确定相同的染色体区域由下降(IBD)共享，我们将在近亲繁殖的POP病例的一小部分(2%)中确定共享IBD。对Norton博士资助的对受影响的PFD同胞的研究获得的数据进行的初步合作分析已经为易感基因在染色体9q上的定位提供了重要证据，并提示至少在1号染色体上有一个其他位点的证据。综上所述，我们将创建一个以人群为基础的手术治疗POP病例资源，我们将寻求现有的和新的方法来识别和定位影响POP的易感基因，我们将开始详细搜索我们已经定位的9号染色体基因。 公共卫生相关性：这项研究在预防产后功能障碍方面具有影响公共健康的重大潜力：我们可能能够确定哪些高危人群可以在年轻时被识别、研究并可能成为预防的目标；在产后功能障碍发展的较后阶段，可以研究并可能对有复发风险的妇女实施特殊干预措施。总有一天，对这些高危人群的识别可能会像家族性风险一样笼统，或者像特定的基因筛查一样具体。

DESCRIPTION (provided by applicant): The investigators propose a unique and powerful collaboration between basic and clinical scientists in Utah to identify genes affecting predisposition to pelvic organ prolapse (POP). The co-PIs both have significant experience, Dr. Norton in Pelvic Floor Disorder (PFD) genetics and Dr. Cannon-Albright in predisposition gene identification. The investigators will access the Utah Population Database, a computerized genealogy of Utah combined with decades of medical data from the two largest healthcare systems in Utah (serving 90% of the state), to identify and recruit surgically treated cases of POP (1,250 cases in 5 years). All POP cases sampled will be genotyped with the Illumina 610Q SNP marker set. The PIs will apply multiple different genetic analyses to this resource of genotyped POP cases to aid in the identification of predisposition genes. The record linkage of medical procedure codes (identifying surgeries performed on each patient) to individual genealogy data allows us to identify all genetic relationships among the POP cases. We will perform genome-wide association analysis, using software we have developed which allows inclusion of both independent and related cases. We will identify all genetic relationships between the sampled POP cases and perform linkage analysis in informative, high-risk POP pedigrees. We will identify chromosomal regions shared Identical by Descent (IBD) in very distantly related cases in these pedigrees, and we will identify IBD sharing within the small subset of POP cases (2%) who are inbred. Initial collaborative analysis of data obtained by Dr. Norton's NIH funded study of affected PFD sib-ships has already provided significant evidence for a predisposition gene localization on chromosome arm 9q, and suggestive evidence for at least one other locus on chromosome 1. In summary, we will create a population-based resource of surgically treated POP cases, we will pursue established and new methods to identify and localize predisposition genes affecting POP, and we will begin a detailed search for the chromosome 9 gene we have localized. PUBLIC HEALTH RELEVANCE: This research has a major potential to affect public health in the prevention of PFDs: we may be able to identify high risk populations who can be identified at a young age, studied and possibly targeted for prevention; and at a later stage in the development of PFDs, special interventions can be studied and possibly implemented in women at risk for recurrence of their condition. Someday, identification of these high risk populations may be as general as familial risk, or as specific as specific gene screening.