IDENTIFICATION OF GENES PREDISPOSING TO PELVIC FLOOR DISORDERS

摘要 研究人员建议在犹他州的基础和临床科学家之间进行一次独特而有力的合作 以确定影响盆腔器官脱垂（POP）易感性的基因。两个共同研究者都有显著的 经验，诺顿博士在骨盆底疾病（PFD）遗传学和加农奥尔布赖特博士在易感性 基因鉴定调查人员将进入犹他州人口数据库，一个计算机化的家谱 结合犹他州两个最大的医疗保健系统（服务于 90%的州），以确定和招募手术治疗的POP病例（5年内1,250例）。所有流行 将用Illumina 610 Q SNP标记集对采样的病例进行基因分型。PI将应用多个 对这种基因型POP病例资源进行不同的遗传分析，以帮助识别 易感基因医疗程序代码的记录链接（识别 每个患者）到个人家谱数据允许我们识别POP之间的所有遗传关系， 例我们将使用我们开发的软件进行全基因组关联分析， 包括独立和相关的案件。我们将确定所有的遗传关系之间的 抽样POP病例，并在信息丰富的高风险POP家系中进行连锁分析。我们将确定 在这些谱系中，在亲缘关系非常远的病例中，染色体区域共享血统相同（IBD）， 我们将在一小部分POP病例（2%）中确定IBD共享，这些病例是近亲繁殖。初始 对诺顿博士的NIH资助的受影响PFD同胞研究所获得的数据进行了合作分析， 已经为染色体臂9 q上的易感基因定位提供了重要证据， 提示1号染色体上至少有一个其他位点的证据。总之，我们将创建一个 基于人群的手术治疗POP病例资源，我们将寻求建立和新的方法， 确定和定位影响POP的易感基因，我们将开始详细搜索 9号染色体的基因定位

Abstract 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.