Pediatric Features of Genetic Predisposition to Polycystic Ovary Syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) has historically been conceptualized as a disorder of the reproductive system in women. However, offspring of women with PCOS begin to show metabolic features of PCOS in childhood, suggestive of childhood manifestations.OBJECTIVE: To identify childhood manifestations of genetic risk for PCOS.DESIGN/SETTING/PARTICIPANTS: We calculated a PCOS polygenic risk score (PRS) for 12,350 girls and boys in four pediatric cohorts - ALSPAC (UK), COPSAC (Denmark), Project Viva (USA), and The HOLBÆK Study (Denmark).MAIN OUTCOME MEASURES: We tested for association of the PRS with PCOS-related phenotypes throughout childhood and with age at pubarche and age at peak height velocity and meta-analyzed effects across cohorts using fixed-effect models.RESULTS: Higher PRS for PCOS was associated with higher BMI in mid-childhood (0.05-kg/m2 increase per 1 SD of PRS, 95% CI: 0.03, 0.07, p=3x10-5) and higher risk of obesity in early childhood (OR: 1.34, 95% CI: 1.13, 1.59, p=0.0009); both persisted through late adolescence (p all ≤0.03). Higher PCOS PRS was associated with earlier age at pubarche (0.85-month decrease per 1 SD of PRS, 95% CI: -1.44, -0.26, p=0.005) and younger age at peak height velocity (0.64-month decrease per 1 SD of PRS, 95% CI: -0.94, -0.33, p=4x10-5).CONCLUSIONS: Genetic risk factors for PCOS are associated with alterations in metabolic and growth and developmental traits in childhood. Thus, PCOS may not simply be a condition that affects reproductive-age women but, rather, one possible manifestation of an underlying condition that affects both sexes starting in early life.