PDF(Pubmed)
Abstract：
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.
摘要：
青春期的时机差异很大，并与以后的健康结果有关。我们对大约80万女性进行了多血统遗传分析，确定1,080个初潮年龄信号。总的来说，这些解释了一个独立样本中11%的性状变异。在多基因风险的顶部和底部1%的女性表现出延迟性早熟和性早熟的风险高出约11倍和约14倍。分别。我们在约200,000名女性中发现了几个具有罕见功能丧失变异的基因，包括ZNF483中的变体，它消除了多基因风险的影响。变异基因作图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MC3R的信号传导，一个关键的营养传感器。与DNA损伤反应相关的基因与绝经时间的共享信号表明，卵巢储备可能是触发青春期的中心信号。我们还强调了身体大小依赖和独立的机制，这些机制可能将生殖时机与以后的生活疾病联系起来。
