AMH signaling pathway variation in PCOS

多囊卵巢综合征(PCOS)是一种内分泌、生殖和代谢的复杂疾病 功能。其患病率为5%-15%，是育龄妇女中最常见的不孕症。 患有多囊卵巢综合征的女性患肥胖症、胰岛素抵抗和2型糖尿病的风险也更高。 因此，多囊卵巢综合征对人口健康产生了强烈的负面影响，为世界卫生组织贡献了50亿美元。 美国每年的医疗负担。它的特点是睾酮水平升高，月经不规律，以及 多囊卵巢。尽管多囊卵巢综合征具有很高的遗传性，但传统的遗传方法已经确定了其中的5% 导致这种综合症的基因变异。罕见的遗传变异和调节元件变异可能 解释了这种“缺失”的遗传性。在对患有多囊卵巢综合征的女性进行的无偏全基因组测序筛查中， 我们鉴定了抗苗勒氏激素基因(AMH)的错义突变。AMH是一种强有力的候选基因 多囊卵巢综合征。它对PCOS的两个中心特征至关重要：卵巢卵泡的募集和发育和雄激素 制作。AMH在多囊卵巢综合征中升高，已被认为是多囊卵巢综合征的生物标志物。在后续研究中，我们 在AMH及其2型受体(AMHR2)中共鉴定出37个罕见的编码和调控变体。这些 在我们的队列中，6.7%的变种显著降低了信号传递能力。没有活动受损的变种 在对照组中观察到，没有观察到PCOS或PCOS中信号活性增加的变体 生育能力正常的女性。我们的研究结果与生育能力正常的女性相比具有非常重要的意义 (χ2=18.0，p=2.20E-05)和非芬兰欧洲人口控制(p&lt；10-8)。我们的发现是 首次鉴定了多囊卵巢综合征的功能验证变体，并提供了强有力的证据 AMH信号级联在多囊卵巢综合征中的关键作用。然而，到目前为止，我们只有 全面筛选AMH及其受体AMH。鉴于大多数基因被认为是 通过高度连接的蜂窝网络影响疾病风险，这是我们的首要假设 AMH信号级联的其他成员也在PCOS中受损，以确定哪些 在多囊卵巢综合征中，AMH信号级联的组成部分受损，以及它们如何影响多囊卵巢综合征的亚型。 将应用创新的、最先进的遗传、分子和生物信息学方法。我们将创建一个 多种族AMH信号级联中约30个成员的推测因果变异的综合目录 并确定了这些变异在多囊卵巢综合征和普通人群中的功能后果。 总而言之，这些研究将是第一次全面评估这一关键的功能遗传变异 多囊卵巢综合征中的信号级联，II。阐明AMH信号级联成员在多囊卵巢综合征和女性中的作用 一般情况下的生殖，以及3.明确表型异质性背后的分子机制 多囊卵巢综合征识别多囊卵巢综合征亚型，从而改善治疗方案。因此，这些研究是关键的一步 在多囊卵巢综合征和女性生殖方面成功实施精准医学。

Polycystic Ovary Syndrome (PCOS) is a complex disorder with endocrine, reproductive, and metabolic features. With a prevalence of 5-15%, it is the most common form of infertility in reproductive age women. Women with PCOS are also at increased risk of developing obesity, insulin resistance and Type 2 Diabetes. Consequently, PCOS has a strong negative impact on the health of the population contributing >$5 billion to the healthcare burden in the US annually. It is characterized by elevated testosterone levels, irregular periods, and polycystic ovaries. Although PCOS is highly heritable, traditional genetic approaches have identified <5% of all the genetic variation contributing to this syndrome. Rare genetic variants and regulatory element variation may account for this “missing” heritability. In an unbiased whole genome sequencing screen of women with PCOS, we identified missense mutations in the anti-Müllerian hormone gene (AMH). AMH is strong candidate gene for PCOS. It is critical to two central features of PCOS: ovarian follicle recruitment and development and androgen production. AMH is elevated in PCOS and has been proposed as a biomarker for PCOS. In follow-up studies, we identified a total of 37 rare coding and regulatory variants in AMH and its type 2 receptor (AMHR2). These variants had significantly reduced signaling capacity in 6.7% of our cohort. No variants with impaired activity were observed in controls and no variants with increased signaling activity were observed in PCOS or reproductively normal womrn. Our results are highly significant relative to reproductively normal women (χ2=18.0, p=2.20E-05) and to non-Finnish European population-based controls (p < 10-8). Our findings are the first identification of functionally validated variants for PCOS and provide strong evidence for a critical role of the AMH signaling cascade in PCOS. However, to date we have only comprehensibly screened AMH and its receptor AMH. Given that most genes are believed to impact disease risk through highly connected cellular networks, it is our overarching hypothesis that other members of the AMH signaling cascade are also impaired in PCOS To ascertain which components of the AMH signaling cascade are impaired in PCOS and how they impact PCOS subphenotypes, we will apply innovative, state-of-the-art genetic, molecular, and bioinformatic approaches. We will create a comprehensive catalog of putative causal variants in ~30 members of the AMH signaling cascade in multiethnic PCOS cohort and determined the functional consequences of these variants in PCOS and the general population. Collectively, these studies will be the first comprehensive evaluation of functional genetic variation of this critical signaling cascade in PCOS, ii. elucidate the role of members of the AMH signaling cascade in PCOS and female reproduction in general, and iii. define the molecular mechanisms that underlie phenotypic heterogeneity of PCOS identifying PCOS subtypes leading to improved treatment options. These studies are thus a critical step towards the successful implementation of Precision Medicine in the context of PCOS and female reproduction.