Genetic Dissection of the Pathophysiology of Polycystic Ovary Syndrome

多囊卵巢综合征病理生理学的基因剖析

• 批准号: 10739832
• 负责人: Jia Zhu
• 金额: $ 16.79万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739832
• 关键词: Address; Adult; Affect; Asthma; Award; Bioinformatics; Biological; Cardiometabolic Disease; Child; Childhood; Clinical; Collaborations; Complex; Computational Biology; Computing Methodologies; Cues; Data; Data Set; Diagnosis; Disease; Dissection; Endocrine; Endocrine System Diseases; Endocrinology; Female infertility; Fertility; Functional disorder; Gene Expression; Gene set enrichment analysis; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic study; Goals; Gonadotropins; Growth; Health; Health Care Costs; Heterogeneity; Hyperandrogenism; Individual; International; Link; Lipids; Longitudinal Studies; Mentorship; Meta-Analysis; Metabolic; Metabolic dysfunction; Methods; Molecular; National Institute of Child Health and Human Development; Outcome; Ovarian; Parents; Pathogenesis; Pathway interactions; Pediatric cohort; Phenotype; Physicians; Physiological; Polycystic Ovary Syndrome; Positioning Attribute; Puberty; Regulation; Reproductive Endocrinology; Risk; Role; Scientist; Sex Bias; Specificity; Subgroup; Testing; Training; Variant; Weight; Woman; aged; androgen biosynthesis; androgenic; biobank; candidate identification; cardiometabolism; cardiovascular disorder risk; clinical care; cohort; experience; folliculogenesis; genetic risk factor; genetic variant; genome wide association study; genome-wide; genomic locus; innovation; insight; insulin secretion; member; men; metabolomics; novel; ovarian dysfunction; phenotypic data; polygenic risk score; precision medicine; prepuberty; reproductive; risk stratification; sex; skills; therapeutic target; trait

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.

项目概要/摘要 多囊卵巢综合症 (PCOS) 是一个主要的健康问题，影响着高达 10% 的育龄妇女 是女性不孕的主要原因。这种复杂、异质的情况与 排卵功能障碍、雄激素过多症和心脏代谢功能障碍，预计造成 80 亿美元的损失 美国每年的医疗费用。 PCOS 与两个卵巢因素（卵泡发生、 促性腺激素分泌和作用、卵巢雄激素生物合成）和非卵巢因素（胰岛素分泌 以及动作、体重和能量调节）。这些影响因素都是相互关联的，并且诱发因素 PCOS 的病因尚不清楚。因此，PCOS 的临床护理目前仅限于管理 多囊卵巢综合症的表现而不是治疗根本原因。本研究的总体假设是 PCOS 是由多种代谢和生殖内分泌途径的扰动引起的，其中一些途径 女性、男性和儿童之间共有一些，而另一些则不同。为了检验这个假设，这个项目将采取 最近完成的全基因组关联研究荟萃分析的优势使数量增加了一倍 影响 PCOS 风险的基因位点。由于这些遗传变异存在于所有个体中，因此 这一发现不仅能够检查多囊卵巢综合症遗传危险因素对女性的表型影响， 还有男人和孩子。该项目利用了英国生物银行的力量，该银行拥有近 400,000 名成年人 在英国，以及四个儿科队列，雅芳父母和儿童纵向研究（N>6,000）， 哥本哈根儿童哮喘研究 (N>500)、Project Viva (N>500) 和 HOLBAEK 研究 （N>4,000）。在成人中，将评估多囊卵巢综合征的遗传风险因素对心脏代谢的性别偏见影响 和其他结果并与 PCOS 相关特征聚类，并且基因集富集分析将用于 获得对这些多囊卵巢综合征遗传风险因素组的机制见解。在儿童中，遗传风险评分（即 估计对 PCOS 的遗传易感性）将被计算并测试与心脏代谢的关联 和雄激素特征以及多种代谢物。该提案有望暗示因果生物学 PCOS 发病机制及其相关特征，这可能允许 将 PCOS 的病因解构为不同的亚组，从而为精确的诊断铺平道路 女性 PCOS 及其相关疾病的诊断、风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，朱博士将获得高级的新技能 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， 以及对生殖内分泌对各种健康状况的影响的深入了解。这 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 独立医师科学家应用创新的计算方法来理解复杂的 生殖内分泌失调。