AMH signaling pathway variation in PCOS

多囊卵巢综合征（PCOS）是一种复杂的内分泌、生殖和代谢紊乱 功能.它的患病率为5- 15%，是育龄妇女最常见的不孕症。 患有PCOS的女性也有增加患肥胖症、胰岛素抵抗和2型糖尿病的风险。 因此，多囊卵巢综合征对人口的健康有很大的负面影响， 美国每年的医疗负担。其特征是睾酮水平升高，月经不规则， 多囊卵巢虽然PCOS是高度遗传的，但传统的遗传方法已经确定了小于5%的所有 导致这种综合症的遗传变异罕见的遗传变异和调控元件变异可能 解释这种“缺失的”遗传性。在对多囊卵巢综合征女性进行无偏倚的全基因组测序筛查时， 我们发现了抗苗勒管激素基因（AMH）的错义突变。抗苗勒氏管激素是抗苗勒氏管炎的强候选基因。 PCOS。它对PCOS的两个中心特征至关重要：卵泡募集和发育以及雄激素 生产AMH在PCOS中升高，已被提议作为PCOS的生物标志物。在后续研究中，我们 鉴定了AMH及其2型受体（AMHR 2）中总共37种罕见的编码和调节变体。这些 在我们的队列中，6.7%的变体具有显著降低的信号传导能力。无活性受损的变体 在对照组中观察到，在PCOS或PCOS患者中没有观察到具有增加的信号传导活性的变体。 生殖正常的妇女。我们的研究结果相对于生育正常的女性来说是非常显著的 （χ2=18.0，p=2.20E-05）和非芬兰欧洲人群为基础的对照（p < 10-8）。我们的研究结果是 首次鉴定出PCOS的功能性变异，并提供了强有力的证据 AMH信号级联在PCOS中的关键作用。然而，到目前为止， AMH及其受体AMH。鉴于大多数基因被认为 通过高度连接的细胞网络影响疾病风险，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 AMH信号级联的组成部分在PCOS中受损，以及它们如何影响PCOS亚表型，我们 将采用创新的、最先进的遗传、分子和生物信息学方法。我们将创建一个 多种族中AMH信号级联的约30个成员中推定的因果变异的综合目录 PCOS队列，并确定这些变异在PCOS和一般人群中的功能后果。 总的来说，这些研究将是第一次全面评估这一关键基因的功能遗传变异。 PCOS中的信号传导级联，ii.阐明AMH信号级联成员在PCOS和女性中的作用 一般的繁殖，和iii.确定表型异质性的分子机制， PCOS识别PCOS亚型，从而改善治疗方案。因此，这些研究是关键的一步， 在PCOS和女性生殖的背景下成功实施精准医学。

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.