KAREN WINER
$2,500
Boston Children's Hospital
Massachusetts
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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.