Pediatric Features of Genetic Predisposition to Polycystic Ovary Syndrome

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. To identify childhood manifestations of genetic risk for PCOS. 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). 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. 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). 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.