AMH signaling pathway variation in PCOS

PCOS 中 AMH 信号通路的变化

基本信息

批准号：
10358620
负责人：
Margrit Urbanek
金额：
$ 61.34万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10358620
关键词：
AMHR2 gene Affect Age Amenorrhea Androgens Antral Aromatase Bioinformatics Biological Assay Biological Markers CYP11A1 gene CYP17A1 gene Candidate Disease Gene Catalogs Code Complex Data Development Disease Down-Regulation Electronic Medical Records and Genomics Network Endocrine Estradiol Estrone Etiology European Evaluation Female Follow-Up Studies Gene Expression Profile Gene Frequency General Population Genes Genetic Genetic Databases Genetic Transcription Genetic Variation Goals Growth Healthcare Heritability Heterogeneity Hormonal Hormones Hyperandrogenism Impairment Infertility Insulin Resistance Link Medical Records Medical center Metabolic Microfluidics Minor Missense Mutation Modeling Molecular Mullerian-inhibiting substance receptor Non-Insulin-Dependent Diabetes Mellitus Obesity Oligomenorrhea Ovarian Ovarian Follicle Participant Periodicity Phenotype Polycystic Ovary Syndrome Prevalence Production Progesterone Regulation Regulatory Element Reporting Reproduction Risk Role Signal Transduction Signaling Protein Steroid biosynthesis Syndrome Testing Testosterone Tissues United States National Institutes of Health Untranslated RNA Variant Woman anovulatory infertility biobank causal variant cohort dehydroepiandrosterone disorder risk epigenetic variation folliculogenesis genetic approach genetic variant genome sequencing granulosa cell improved in silico innovation loss of function mRNA Expression member men mullerian-inhibiting hormone multi-ethnic next generation sequencing population based population health precision medicine protein expression receptor recruit reproductive support network theca cell whole genome

项目摘要

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.

多囊卵巢综合征（PCOS）是一种复杂的疾病，内分泌，生殖和代谢特征。它的患病率为5-15％，这是复制年龄妇女中最常见的不育症形式。患有PCOS的女性也有增加肥胖，胰岛素抵抗和2型糖尿病的风险。因此，PCOS对人口的健康有很大的负面影响，对人口的健康贡献了50亿美元每年在美国的医疗保健伯恩。它的特征是睾丸激素水平升高，不规则周期和多囊卵巢。尽管PCOS是高度遗传的，但传统的遗传方法已经确定了<5％导致该综合征的遗传变异。罕见的遗传变异和调节元件变异可能解释这种“缺失”的遗传力。在PCOS女性的无偏见的整个基因组测序屏幕中，我们确定了抗肿瘤激素基因（AMH）中的错义突变。 AMH是强大的候选基因 PCOS。这对于PCOS的两个主要特征至关重要：卵巢卵泡募集和开发和雄激素生产。 AMH在PCOS中升高，并已被提议作为PCOS的生物标志物。在后续研究中，我们在AMH及其2型受体（AMHR2）中，总共确定了37种稀有编码和调节变体。这些在我们的队列的6.7％中，变体的信号传导能力显着降低。没有活动受损的变体在对照中观察到，在PCOS或生殖正常的子宫。相对于生殖正常女性，我们的结果非常重要（χ2= 18.0，p = 2.20E-05）和非欧洲基于欧洲人群的对照（p <10-8）。我们的发现是首次识别PCOS功能验证的变体，并提供有力的证据对于PCOS中AMH信号级联的关键作用。但是，迄今为止我们只有完全筛选AMH及其接收器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的风险，这是我们的总体假设 PCOS中也损害了AMH信号级联的其他成员，以确定哪个 AMH信号级联的组件在PCOS中受到损害，以及它们如何影响PCOS亚表格型，我们我们将采用创新，最先进的遗传，分子和生物信息学方法。在多民族中，AMH信号级联的大约30个成员的推定因果变体的全面目录 PCOS队列并确定了PCOS和一般人群中这些变体的功能后果。总的来说，这些研究将是对该关键功能遗传变异的首次全面评估 PCOS中的信号级联，ii。阐明AMH信号级联对PCOS和女性的作用总体而言，繁殖和III。定义基于表型异质性的分子机制 PCOS识别PCOS亚型，从而改善了治疗选择。因此，这些研究是关键的一步在PCOS和女性繁殖的背景下成功实施精密医学。