Effects of Maternal Genetic Risk Factors for Polycystic Ovary Syndrome on Birth and Childhood Outcomes in Offspring

/ ABSTRACT Polycystic ovary syndrome (PCOS) is a major health concern that affects up to 10% of reproductive-aged women and incurs an estimated economic burden of $8 billion in annual healthcare costs in the U.S. This complex, heterogenous condition is characterized by ovulatory dysfunction and hyperandrogenism and is associated with increased risk for metabolic dysregulation. Not included in cost estimates are the impact on offsprings of mothers with PCOS, who are at increased risk for adverse birth outcomes as well as the metabolic and androgenic features of PCOS. Evidence from clinical studies suggest that maternal PCOS could have causal biological effects in the intrauterine period that lead to adverse child outcomes; however, the role of PCOS genetic factors in the development of these adverse child outcomes is not known. Distinguishing between the contributing roles of the intrauterine environment and transmitted PCOS genetic factors to these adverse offspring outcomes would directly impact the timing (peri- vs. postnatal) and population (mothers vs. offspring) of targeted interventions to prevent PCOS and its associated comorbidities in children. The central hypothesis for this proposal is that maternal PCOS genetics, by acting through pre- and perinatal factors, play an integral role in the development of adverse birth outcomes and childhood metabolic and androgenic phenotypes in offspring. 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 and the increasing availability of mother-offspring data in biobanks. This project leverages the power of 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 Growing Up Today Study (N>1,000). In mothers and their offspring, PCOS genetic risk scores (i.e., estimated genetic susceptibility to PCOS) will be calculated. The effect of maternal PCOS genetic risk on the relationship between perinatal factors and adverse birth outcomes will be assessed, and the pre- and perinatal factors associated with maternal PCOS genetic risk that influence metabolic and androgenic phenotypes in offspring will be defined. This proposal promises to dissect the roles of transmitted PCOS genetic factors and the intrauterine environment in the development of adverse birth and childhood outcomes, and thereby pave the way for a precision-medicine approach to care that breaks the transgenerational cycle of PCOS and its related comorbidities. Project Number: 1R03HD118217-01 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Jia Zhu | Institution: BOSTON CHILDREN'S HOSPITAL, BOSTON, MA | Award Amount: $178,000 | Activity Code: R03 | Study Section: Reproduction, Andrology, and Gynecology Study Section[CHHD-R] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R03HD11821701