青春期提前或推迟可能导致成年后罹患疾病，包括癌症、肥胖、2 型糖尿病、代谢紊乱、骨折和精神病理学。因此，了解青春期的年龄至关重要，因为它可以作为未来疾病的风险因素。根据标准化坦纳量表，青春期发育将男孩和女孩分为五个性成熟阶段。我们对“生长和肥胖智利队列研究”队列进行了全基因组关联研究（GWAS），该队列由主要是欧洲和美洲原住民血统的混合儿童组成。使用将事件发生时间数据与体重指数（BMI）纵向轨迹相结合的联合模型，我们确定了与坦纳阶段对之间表型转变相关的遗传变异。我们发现了 42 美元的新颖显着关联，其中大多数是男孩。男孩 Tanner $3\rightarrow 4$ 转变的 GWAS 捕获了生长相关基因 LARS2 和 LIMD1 基因周围的关联峰，前者突变时会导致卵巢功能障碍。相关变体是表达和剪接数量性状基因座调节多个组织中的基因表达和选择性剪接。此外，较高的美洲原住民个体遗传血统比例预示着男孩的青春期开始时间明显提前，但女孩则不然。最后，联合模型确定了与几个 Tanner 阶段的转变显着相关的纵向 BMI 参数，证实了 BMI 与青春期时间的关联。© 作者 2024。由牛津大学出版社出版。版权所有。如需权限，请发送电子邮件至：journals.permissions@oup.com。

Early or late pubertal onset can lead to disease in adulthood, including cancer, obesity, type 2 diabetes, metabolic disorders, bone fractures, and psychopathologies. Thus, knowing the age at which puberty is attained is crucial as it can serve as a risk factor for future diseases. Pubertal development is divided into five stages of sexual maturation in boys and girls according to the standardized Tanner scale. We performed genome-wide association studies (GWAS) on the "Growth and Obesity Chilean Cohort Study" cohort composed of admixed children with mainly European and Native American ancestry. Using joint models that integrate time-to-event data with longitudinal trajectories of body mass index (BMI), we identified genetic variants associated with phenotypic transitions between pairs of Tanner stages. We identified $42$ novel significant associations, most of them in boys. The GWAS on Tanner $3\rightarrow 4$ transition in boys captured an association peak around the growth-related genes LARS2 and LIMD1 genes, the former of which causes ovarian dysfunction when mutated. The associated variants are expression and splicing Quantitative Trait Loci regulating gene expression and alternative splicing in multiple tissues. Further, higher individual Native American genetic ancestry proportions predicted a significantly earlier puberty onset in boys but not in girls. Finally, the joint models identified a longitudinal BMI parameter significantly associated with several Tanner stages' transitions, confirming the association of BMI with pubertal timing.© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.