英国剑桥生物医学校区代谢科学研究所John R. B. Perry等合作近期取得重要工作进展，他们研究通过等位基因频谱了解青春期时间的遗传复杂性。相关研究成果2024年7月1日在线发表于《自然—遗传学》杂志上。

据介绍，女性青春期的时间差异很大，并且与以后的健康结果有关。

研究人员对大约80万名女性进行了多祖先基因分析，确定了1080个月经初潮时的年龄信号。总的来说，这些解释了独立样本中11%的性状变异。处于多基因风险最高和最低1%的女性患性早熟和迟发性早熟的风险分别高出约11倍和约14倍。在约20万名女性中，研究人员发现了几个携带罕见功能丧失变异的基因，包括ZNF483中的变异，它消除了多基因风险的影响。

基因定位方法的变体和小鼠促性腺激素释放激素神经元RNA测序涉及665个基因，包括一种未表征的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同信号表明，卵巢储备可能是触发青春期的集中信号。研究人员还强调了体型依赖和独立的机制，这些机制可能将生殖时间与晚年疾病联系起来。

附：英文原文

Title: Understanding the genetic complexity of puberty timing across the allele frequency spectrum

Author: Kentistou, Katherine A., Kaisinger, Lena R., Stankovic, Stasa, Vaudel, Marc, Mendes de Oliveira, Edson, Messina, Andrea, Walters, Robin G., Liu, Xiaoxi, Busch, Alexander S., Helgason, Hannes, Thompson, Deborah J., Santoni, Federico, Petricek, Konstantin M., Zouaghi, Yassine, Huang-Doran, Isabel, Gudbjartsson, Daniel F., Bratland, Eirik, Lin, Kuang, Gardner, Eugene J., Zhao, Yajie, Jia, Raina Y., Terao, Chikashi, Riggan, Marjorie J., Bolla, Manjeet K., Yazdanpanah, Mojgan, Yazdanpanah, Nahid, Bradfield, Jonathan P., Broer, Linda, Campbell, Archie, Chasman, Daniel I., Cousminer, Diana L., Franceschini, Nora, Franke, Lude H., Girotto, Giorgia, He, Chunyan, Jrvelin, Marjo-Riitta, Joshi, Peter K., Kamatani, Yoichiro, Karlsson, Robert, Luan, Jianan, Lunetta, Kathryn L., Mgi, Reedik, Mangino, Massimo, Medland, Sarah E., Meisinger, Christa, Noordam, Raymond, Nutile, Teresa, Concas, Maria Pina, Polaek, Ozren, Porcu, Eleonora, Ring, Susan M., Sala, Cinzia, Smith, Albert V., Tanaka, Toshiko, van der Most, Peter J., Vitart, Veronique, Wang, Carol A., Willemsen, Gonneke, Zygmunt, Marek, Ahearn, Thomas U., Andrulis, Irene L.

Issue&Volume: 2024-07-01

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.

DOI: 10.1038/s41588-024-01798-4

Source: https://www.nature.com/articles/s41588-024-01798-4