Dissecting PCOS Physiology by Defining Phenotypes Associated with PCOS Genetic Risk Factors in Men and Children

项目总结/摘要 多囊卵巢综合征（PCOS）是一个主要的健康问题，影响到10%的所有 育龄妇女。这种复杂的异质性疾病的特征通常是三位一体的 排卵功能障碍、高雄激素血症和心脏代谢功能障碍，估计造成43亿美元的损失。 美国每年的医疗费用。尽管进行了广泛的生理和遗传研究， 由于对该疾病的病理生理学的不完全理解而仍然受到限制。现有证据 表明PCOS与卵巢相关因素（促性腺激素分泌和作用， 卵泡发生，雄激素生物合成）和卵巢非依赖性因子（肾上腺雄激素生物合成， 胰岛素分泌和作用，体重和能量调节），但这些是激发事件， 哪些是次要后果尚不清楚。这项研究的总体假设是， 通常主要是女性生殖障碍，但也可能主要是高雄激素症的一种情况 和/或心脏代谢失调，卵巢功能障碍作为次要后果。为了验证这一 假设，该项目将利用最近基因组广泛关联研究（GWAS）， 发现了许多影响PCOS风险的遗传变异。因为这些基因变异存在于 这一发现为研究遗传风险的表型效应提供了独特的机会。 男性和青春期前儿童的PCOS因素，而不受卵巢因素的影响。这个项目 利用英国生物银行的力量，这是一个基于人口的队列，由英国176，367名无关男性组成， 两个纵向儿科出生队列，哥本哈根儿童哮喘研究（COPSAC）， 丹麦的558名儿童和英国的雅芳父母和儿童纵向研究（ALSPAC）， 6,791名儿童。将计算男性的遗传风险评分（即估计的PCOS遗传易感性） 来自英国生物银行和来自COPSAC和ALSPAC的青春期前儿童， 高雄激素和心脏代谢表型。描述男性和儿童的表型， 携带PCOS的遗传风险因素将为确定特定的生物学途径提供起点 PCOS发病机制的基础，允许未来开发PCOS的靶向治疗， 加深我们对PCOS遗传危险因素的儿科表现的理解。 该奖学金培训计划包括一个由Joel赫什霍恩博士和Dr. Yee-Ming Chan在布罗德研究所和波士顿儿童医院（BCH）内分泌科。 博士赫什霍恩的实验室和布罗德研究所将为朱博士提供人类遗传学方面的广泛培训， 多基因疾病和计算生物学和生物信息学。陈博士的实验室将为朱博士提供 科学和临床儿科生殖内分泌学培训。儿科内分泌学研究会 该项目将为朱医生提供儿科内分泌临床实践方面的特殊培训。

PROJECT SUMMARY/ ABSTRACT Polycystic ovarian syndrome (PCOS) is a major health concern that affects up to 10% of all reproductive-aged women. This complex, heterogeneous condition is often characterized by a triad of ovulatory dysfunction, hyperandrogenism, and cardiometabolic dysfunction and incurs an estimated $4.3 billion in annual U.S. healthcare costs. Despite extensive physiologic and genetic studies, the treatment of PCOS remains limited by an incomplete understanding of the pathophysiology of the disorder. Existing evidence suggests that PCOS is associated with both ovarian-related factors (gonadotropin secretion and action, folliculogenesis, androgen biosynthesis) and ovarian-independent factors (adrenal androgen biosynthesis, insulin secretion and action, weight and energy regulation), but which of these are the inciting events and which are the secondary consequences are unknown. The overall hypothesis for this study is that PCOS is not always primarily a disorder of female reproduction, but rather can be primarily a condition of hyperandrogenism and/or cardiometabolic dysregulation, with ovarian dysfunction as a secondary consequence. To test this hypothesis, this project will take advantage of a recent genome wide-association study (GWAS) that discovered numerous genetic variants that influence PCOS risk. Because these genetic variants are present in all individuals, this discovery provides a unique opportunity to study the phenotypic effects of genetic risk factors for PCOS in men and prepubertal children without the influence of ovarian factors. This project leverages the power of the UK Biobank, a population-based cohort of 176,367 unrelated men in the UK, and two longitudinal pediatric birth cohorts, the Copenhagen Studies on Asthma in Childhood (COPSAC) in Denmark with 558 children and the Avon Longitudinal Study of Parents and Children (ALSPAC) in the UK with 6,791 children. Genetic risk scores (i.e. estimated genetic susceptibility to PCOS) will be calculated in men from the UK Biobank and prepubertal children from COPSAC and ALSPAC and tested for associations with hyperandrogenic and cardiometabolic phenotypes. Characterizing the phenotypes in men and children who carry genetic risk factors for PCOS will provide a starting point for identifying specific biological pathways underlying the pathogenesis of PCOS, allow for the future development of targeted therapies for PCOS, and deepen our understanding of pediatric manifestations of genetic risk factors for PCOS. The fellowship training plan consists of a co-mentoring team composed of Dr. Joel Hirschhorn and Dr. Yee-Ming Chan at the Broad Institute and the Division of Endocrinology at Boston Children’s Hospital (BCH). Dr. Hirschhorn’s lab and the Broad Institute will provide Dr. Zhu with extensive training in human genetics of polygenic disease and computational biology and bioinformatics. Dr. Chan’s lab will provide Dr. Zhu with training in scientific and clinical pediatric reproductive endocrinology. The pediatric endocrinology fellowship program at BCH will provide Dr. Zhu with exceptional training in the clinical practice of pediatric endocrinology.