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

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.

Objectives

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.

Results

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).

Conclusions

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.