The Genetics of Polycystic Ovary Syndrom

描述（由申请人提供）：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。这种疾病的主要特征是：月经周期不规则，高雄激素血症和超声显示的多囊卵巢模式。此外，患有PCOS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。该研究确定了4号染色体上的一种变异，该变异在冰岛病例对照队列中达到全基因组意义，并在表型相同的波士顿队列中复制。该提案的广泛目标是通过精细映射来识别该风险变量标记的因果变量。我们还将使用表达研究和/或蛋白质功能测定来检查因果变体的功能效应。最后，我们将检查由基因型定义的表型特征。 具体目标1将检查4号染色体变异周围的区域，以确定影响蛋白质产生或基因表达的致病变异。将使用HapMap和1000个基因组项目中常见的单核苷酸多态性（SNP）进行精细定位。此外，将对与相关变体连锁不平衡的基因的外显子和启动子区进行大量测序，以鉴定可能影响蛋白质产生或基因表达的罕见变体。具体目标2将使用PI在过去6年中收集的广泛数据库，剖析PCOS、对照、男性和绝经后女性中基因型赋予的表型。具体目标3将检查携带者和非携带者中具有4号染色体变异的LD中的两个候选基因的表达，以确定感兴趣的基因。当鉴定出致病变体时，还将使用定量PCR检查表达以鉴定变体在淋巴母细胞样细胞系数据库中以及在体外脂肪、卵泡膜和外周白色血细胞中的功能效应。将使用信号传导测定和细胞系统和动物模型中变体的过表达或敲低来评估编码序列因果变体和罕见变体。 这些研究将揭示PCOS全基因组病例对照关联研究中发现的第一个已知变异标志的致病变异和基因。该建议有可能阐明PCOS的病因。这些信息由来已久，对于为这种非常常见的疾病及其不良健康后果提供更好的诊断和治疗信息至关重要。

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.