Genetic Dissection of the Pathophysiology of Polycystic Ovary Syndrome

项目摘要/摘要 多囊卵巢综合征(PCOS)是一种主要的健康问题，影响多达10%的育龄妇女 这是女性不孕不育的主要原因。这种复杂的、异质性的疾病与 排卵功能障碍、高雄激素血症和心脏代谢性功能障碍，估计造成80亿美元 在美国年度医疗保健成本中。多囊卵巢综合征与两种卵巢因素的改变有关(卵泡形成， 促性腺激素的分泌和作用、卵巢雄激素的生物合成)和非卵巢因素(胰岛素分泌 以及行动、体重和能量监管)。这些促成因素都是相互关联的，而煽动 多囊卵巢综合征的原因尚不清楚。因此，目前对多囊卵巢综合征的临床护理仅限于管理 多囊卵巢综合征的表现，而不是治疗根本原因。这项研究的总体假设是 多囊卵巢综合征是由多种代谢和生殖内分泌途径的扰动引起的，其中一些 在女性、男性和儿童之间是共享的，其他是不同的。为了检验这一假设，这个项目将需要 最近完成的全基因组关联研究荟萃分析的优势，它使数字翻了一番 影响多囊卵巢综合征风险的遗传基因座。因为这些遗传变异在所有个体中都存在，所以 这一发现使人们能够检查遗传风险因素对多囊卵巢综合征的表型影响，不仅在女性中，而且在 还有男人和孩子。该项目利用了英国生物银行的力量，该银行由近40万名成年人组成 在英国，以及四个儿科队列，雅芳对父母和孩子的纵向研究(N&GT；6000)， 关于儿童哮喘的哥本哈根研究(N&gt；500)、活生生的项目(N&gt；500)和Holbaek研究 (N&GT；4,000)。在成人中，多囊卵巢综合征的遗传风险因素将被评估性别偏见对心脏代谢的影响 和其他结果，并与多囊卵巢综合征相关性状进行聚类，以及基因集浓缩分析将用于 获得对这些组多囊卵巢综合征遗传风险因素的机械性见解。在儿童中，遗传风险分数(即， 多囊卵巢综合征的估计遗传易感性)将被计算并测试与心脏代谢的相关性 和雄激素特征以及各种代谢物。这项提议承诺牵涉到因果生物学 多囊卵巢综合征发病机制及其相关特征，这可能允许 将多囊卵巢综合征的病因解构为不同的亚组，从而为精确地- 女性多囊卵巢综合征及其相关疾病的诊断、危险分层和治疗的医学方法 成人和儿童的情况。通过这项提议，朱博士将获得先进的 计算遗传学方法，应用计算生物学和生物信息学原理的经验， 以及对生殖内分泌学对各种健康状况的影响的深刻理解。这个 K08奖将为朱博士提供关键的培训和指导，以实现她成为一名 独立的内科医生-科学家应用创新的计算方法来理解复杂性 生殖内分泌紊乱。

PROJECT SUMMARY/ ABSTRACT Polycystic ovary syndrome (PCOS) is a major health concern that affects up to 10% of all reproductive-aged women and is the leading cause of female infertility. This complex, heterogeneous condition is associated with ovulatory dysfunction, hyperandrogenism, and cardiometabolic dysfunction and incurs an estimated $8 billion in annual U.S. healthcare costs. PCOS is associated with alterations in both ovarian factors (folliculogenesis, gonadotropin secretion and action, ovarian androgen biosynthesis) and non-ovarian factors (insulin secretion and action, weight and energy regulation). These contributing factors are all interconnected, and the inciting causes of PCOS remains unknown. As a result, the clinical care of PCOS is currently confined to managing the manifestations of PCOS rather than treating the underlying causes. The overall hypothesis for this study is that PCOS arises from the perturbation of multiple metabolic and reproductive endocrine pathways, some of which are shared and others distinct between women, men, and children. To test this hypothesis, this project will take advantage of a recently completed genome wide-association study meta-analysis that has doubled the number of genetic loci that influence PCOS risk. Because these genetic variants are present in all individuals, this discovery enables examination of the phenotypic effects of genetic risk factors for PCOS in not just women but also men and children. This project leverages the power of the UK Biobank, a cohort of nearly 400,000 adults in the UK, and four pediatric cohorts, Avon Longitudinal Study of Parents and Children (N>6,000), Copenhagen Studies on Asthma in Childhood (N>500), Project Viva (N>500), and the HOLBAEK Study (N>4,000). In adults, genetic risk factors for PCOS will be assessed for sex-biased effects on cardiometabolic and other outcomes and clustered with PCOS-related traits, and gene-set enrichment analysis will be used to gain mechanistic insights into these groups of PCOS genetic risk factors. In children, genetic risk scores (i.e., estimated genetic susceptibility to PCOS) will be calculated and tested for associations with cardiometabolic and androgenic traits as well as diverse metabolites. This proposal promises to implicate causal biological mechanisms underlying the pathogenesis of PCOS and its associated features, which could allow for the deconstruction of the causes of PCOS into distinct subgroups, and thereby pave the way for a precision- medicine approach to the diagnosis, risk stratification, and treatment of PCOS in women and its associated conditions in adults and children. Through this proposal, Dr. Zhu will attain new skills in advanced computational genetic methods, experience in applying principles in computational biology and bioinformatics, and a deep understanding of the impact of reproductive endocrinology on a variety of health conditions. The K08 award will provide Dr. Zhu the critical training and mentorship to achieve her goal of becoming an independent physician-scientist applying innovative computational methods to understand complex reproductive endocrine disorders.