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.

项目摘要/摘要 多囊卵巢综合征（PCOS）是一个主要的健康问题，最多影响所有生殖时代的10％ 妇女，是女性不育的主要原因。这种复杂的，异构的条件与 排卵功能障碍，超雄激素和心脏代谢功能障碍，估计有80亿美元 在年度美国医疗保健费用中。 PCOS与两个卵巢因子的改变有关（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 和动作，体重和能量调节）。这些促成因素都是互连的，煽动 PCOS的原因仍然未知。结果，PCOS的临床护理目前仅限于管理 PCOS的表现而不是处理根本原因。这项研究的总体假设是 PCOS源于多种代谢和生殖内分泌途径的扰动，其中一些 共享，其他男女之间的不同。为了检验这一假设，该项目将采取 最近完成的基因组广泛关联研究荟萃分析的优势使数量增加了一倍 影响PCOS风险的遗传基因座。因为这些遗传变异存在于所有个体中，所以 发现可以检查遗传危险因素对PCOS对女性的表型影响，而且还可以检查 也是男人和孩子。该项目利用了英国生物银行的力量，这是一个近40万成人组成的队列 在英国和四个小儿同伙，对父母和孩子的雅芳纵向研究（n> 6,000）， 哥本哈根关于儿童哮喘的研究（N> 500），Viva项目（n> 500）和Holbaek研究 （n> 4,000）。在成年人中，将评估PCOS的遗传危险因素对性偏见对心脏代谢的影响 以及其他结果，并与PCOS相关的特征聚集，基因 - 富集分析将用于 对这些PCOS遗传危险因素进行机械洞察力。在儿童中，遗传风险评分（即 估计对PCOS的遗传敏感性）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产物。该提案有望暗示因果生物学 PCOS发病机理及其相关特征的基础机制，这可以允许 将PCOS的原因解构为不同的亚组，从而为精确铺平了道路 妇女及其相关的PCOS诊断，风险分层和治疗的医学方法 成人和儿童的条件。通过此建议，朱博士将获得高级的新技能 计算遗传方法，在计算生物学和生物信息学中应用原理方面的经验， 并深刻了解生殖内分泌学对各种健康状况的影响。这 K08 Award将为朱博士提供关键的培训和指导，以实现她成为一个目标的目标 独立医师科学家采用创新计算方法来理解复杂 生殖内分泌疾病。