Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

青春期时间差异很大，并且与以后的健康结果相关。我们对约 800,000 名女性进行了多祖先遗传分析，识别了 1,080 个初潮年龄信号。总的来说，这些解释了独立样本中 11% 的性状变异。多基因风险最高和最低 1% 的女性青春期延迟和性早熟的风险分别高出约 11 倍和约 14 倍。我们在约 200,000 名女性中发现了一些含有罕见功能丧失变异的基因，其中包括 ZNF483 的变异，它消除了多基因风险的影响。变异基因图谱方法和小鼠促性腺激素释放激素神经元 RNA 测序涉及 665 个基因，包括一个未表征的 G 蛋白偶联受体 GPR83，它放大了关键营养传感器 MC3R 的信号传导。参与 DNA 损伤反应的基因与更年期时间的共享信号表明，卵巢储备可能集中发出信号来触发青春期。我们还强调了与体型相关和独立的机制，这些机制可能将生殖时间与晚年疾病联系起来。