The Genetics of Polycystic Ovary Syndrom

描述(申请人提供)：多囊卵巢综合征(PCOS)是育龄妇女最常见的内分泌疾病，但其病因尚不清楚。这种疾病的定义是其基本特征：月经周期不规律，高雄激素血症和超声下的多囊卵巢模式。此外，患有多囊卵巢综合征的妇女患不孕症、子宫内膜癌、2型糖尿病和心血管危险因素的风险增加。我们与冰岛的deCODE合作完成了一项全基因组关联研究。这项研究发现了4号染色体上的一个变异，在冰岛的病例对照队列中达到全基因组意义，并在波士顿的一个相同表型的队列中复制。这项建议的总体目标是通过精细的映射来确定该风险变量所标记的因果变量。我们还将通过表达研究和/或蛋白质功能分析来检验因果变体的功能效应。最后，我们将检查由基因定义的表型特征。特定目标1将检查4号染色体变异周围的区域，以确定影响蛋白质生产或基因表达的因果变异。将使用HapMap和1000基因组项目中的常见单核苷酸多态(SNPs)进行精细绘图。此外，与相关变异连锁不平衡的基因的外显子和启动子区域将被大量测序，以识别可能影响蛋白质生产或基因表达的罕见变异。具体目标2将利用过去6年由PI收集的广泛数据库，剖析PCOS、对照组、男性和绝经后妇女中由基因赋予的表型。具体目标3将检测带有4号染色体变异的LD中两个候选基因在携带者和非携带者中的表达，以确定感兴趣的基因。当确定一个原因变异体时，还将利用定量聚合酶链式反应来确定变异体(S)在淋巴母细胞系数据库以及体外脂肪、卵泡膜和外周血白细胞中的功能效应。编码序列、因果变异体和稀有变异体将通过信号分析以及在细胞系统和动物模型中的过度表达或敲除来评估。这些研究将揭示由多囊卵巢综合征全基因组病例对照关联研究中发现的第一个已知变异所标记的因果变异和基因。这项提议有可能阐明多囊卵巢综合征的病因。这些信息已经出现了很长时间，对于为这种具有不利健康后果的非常常见的疾病提供更好的诊断和治疗信息至关重要。 与公共卫生相关：多囊卵巢综合征是一种月经不调和雄激素升高的疾病，具有患糖尿病、高血压和血脂升高的高风险。我们现在已经在全基因组关联研究中发现了一种与多囊卵巢综合征相关的遗传变异，并将试图确定其原因变异和它所标记的基因。发现易患多囊卵巢综合征的变异和/或基因(S)将确定病因，并将提供一个新的靶点，为十分之一的育龄妇女开发新的治疗方法。

DESCRIPTION (provided by applicant): Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive age women, yet its etiology is poorly understood. The disorder is defined by its cardinal features: irregular menstrual cycles, hyperandrogenism and a polycystic ovary pattern on ultrasound. In addition, women with PCOS have increased risk for infertility, endometrial cancer, type 2 diabetes and cardiovascular risk factors. We completed a genome-wide association study in collaboration with deCODE in Iceland. The study identified a variant on chromosome 4 reaching genomewide significance in an Icelandic case control cohort and replicating in an identically phenotyped Boston cohort. The broad goal of this proposal is to identify the causal variant that this risk variant marks through fine mapping. We will also examine the functional effects of the causal variant using expression studies and/or assays of protein function. Finally, we will examine the phenotypic features defined by the genotype. Specific Aim 1 will examine the region around the chromosome 4 variant to identify the causal variant that affects protein production or gene expression. Fine mapping will be performed using common single nucleotide polymorphisms (SNPs) in the HapMap and 1000 genomes projects. In addition, the exons and promoter regions of genes in linkage disequilibrium with the associated variant will be sequenced in large numbers to identify rare variants that may affect protein production or gene expression. Specific Aim 2 will dissect the phenotype conferred by the genotype in PCOS, controls, males and postmenopausal women using an extensive database assembled by the PI over the past 6 years. Specific Aim 3 will examine expression of two candidate genes in LD with the chromosome 4 variant in carriers and non-carriers to determine the gene of interest. When a causal variant is identified, expression will also be examined to identify a functional effect of variant(s) in a lymphoblastoid cell line database and in adipose, theca and peripheral white blood cells in vitro using quantitative PCR. Coding sequence causal variants and rare variants will be assessed using signaling assays and overexpression or knock-down of the variants in cell systems and animal models. These studies will uncover the causal variant and gene that is marked by the first known variant identified in a genome-wide case control association study of PCOS. The proposal has the potential to illuminate the etiology of PCOS. Such information has been long in coming and is essential to provide better diagnostic and treatment information for this very common disorder with its adverse health consequences. PUBLIC HEALTH RELEVANCE: Polycystic ovary syndrome is a disorder of irregular menses and elevated androgens that carries a high risk for diabetes, hypertension and elevated lipids. We have now discovered a genetic variant that is associated with polycystic ovary syndrome in a genome-wide association study and will try to determine the causal variant and gene it marks. Discovering the variants and/or gene(s) that predispose to PCOS will determine an etiology and will provide a novel target to develop new treatments for the 1 in 10 reproductive age women it affects.