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 mento...