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Jia Zhu, MD






Boston Children's Hospital




Jia Zhu, MD*, Joel N. Hirschhorn, MD, PhD*, Yee-Ming Chan, MD, PhD*

Principal Investigator

Yee-Ming Chan, MD, PhD


Early Metabolic and Androgenic Features of Genetic Risk Factors for Polycystic Ovary Syndrome

Polycystic ovarian syndrome (PCOS) affects up to 10% of women of reproductive age and is the leading cause of female infertility. Though not a diagnostic criterion, cardiometabolic dysfunction with insulin resistance, dyslipidemia, and/or obesity is often a life-long comorbidity.

Because the understanding of the pathophysiology of PCOS is incomplete, clinical care is currently confined to managing the manifestations of PCOS rather than treating the underlying cause. Existing clinical and genetic evidence have shown that genetic risk for PCOS is associated with cardiometabolic and hyperandrogenic conditions in both women and men.

My work shows that genetic risk factors for PCOS have sex-biased effects in childhood. Further characterizing and understanding the molecular pathways that underlie these genetic risk factors in women, men, and children could not only shed light on the pathogenesis of PCOS, but also could provide insights into how to intervene to prevent PCOS and its associated conditions in children.


Polycystic ovary syndrome (PCOS) is a heterogeneous and common condition that is associated with ovulatory dysfunction, hyperandrogenism, and cardiometabolic dysfunction. In children, premature adrenarche, a common condition characterized by early production of adrenal androgens and increased risk of metabolic dysfunction, has been proposed to be a precursor to PCOS in girls.



We sought to identify cardiometabolic and androgenic conditions in children associated with PCOS genetic risk factors previously discovered in women.

Methods: We calculated a PCOS polygenic risk score (PRS) for 5,968 children in the Avon Longitudinal Study of Parental and Children. We used linear regression to assess for associations between the PCOS PRS and age at pubarche and body mass index throughout childhood.



A higher PCOS PRS was associated with a younger age at pubarche (effect size=1.0 month decrease per 1 SD increase in the PCOS PRS, p=0.001). This effect was more pronounced in boys than girls (1.2 months younger, p=0.017 vs.  0.9 months younger, p=0.022, respectively). A higher PCOS PRS was associated with a higher BMI SDS as early as 7 years of age (effect size=0.04 SDS per 1 SD increase in the PCOS PRS, p=0.003). At 10 years of age, the effect of a higher PCOS PRS on BMI was greater in girls than boys (0.10 SDS, p=2×10-6 vs. 0.06 SDS, p=0.01, respectively).



By demonstrating associations between PCOS genetic risk factors and cardiometabolic and androgenic phenotypes in children, we have shown that genetic risk factors for PCOS, a disorder of adult women, can result in early perturbations in the biological pathways that underlie PCOS in children with sex-biased effects. Future dissection of the underlying molecular pathways will inform future strategies to prevent, halt, and reverse these perturbations before the development of PCOS and its related conditions.

Research Context