Endocrine Abstracts

Pubertal timing varies widely and influences lifelong health. We conducted a multi-ancestry GWAS in ~800,000 women, identifying 1,080 genetic signals for age at menarche (AAM), explaining 11% of trait variance. Extreme polygenic scores correlated with significantly altered puberty timing. Exome-wide analyses in 220,000 women identified rare variants, including in ZNF483, which nullified polygenic effects. Functional analyses implicated 665 genes, including GPR83, a GPCR enhancing MC3R signaling, a key puberty regulator. Shared genetic signals with menopause and DNA damage response genes suggest ovarian reserve integrity may influence pubertal onset. We also identified body size-dependent and independent pathways linking puberty timing to metabolic disease risk. These findings illuminate the genetic architecture of puberty, highlighting interactions between common and rare variants and their impact on reproductive health and disease susceptibility.