STUDY QUESTION Does fetal genetically determined birth weight associate with the timing of puberty? SUMMARY ANSWER Lower fetal genetically determined birth weight was causally associated with an earlier onset of puberty, independent of the indirect effects of the maternal intrauterine environment. WHAT IS KNOWN ALREADY Previous Mendelian randomization (MR) studies have indicated a potential causal link between birth weight, childhood BMI, and the onset of puberty. However, they did not distinguish between genetic variants that have a direct impact on birth weight through the fetal genome (referred to as fetal genetic effects) and those that influence birth weight indirectly by affecting the intrauterine environment (known as maternal genetic effects). It is crucial to emphasize that previous studies were limited because they did not account for the potential bias caused by unaddressed correlations between maternal and fetal genetic effects. Additionally, the proportion of birth weight variation explained by the fetal genome is considerably larger than that of the maternal genome. STUDY DESIGN, SIZE, DURATION We performed two-sample MR analyses to investigate the causal effect of fetal genetically determined birth weight on puberty timing using summary data from large-scale genome-wide association studies (GWASs) in individuals of European ancestry. PARTICIPANTS/MATERIALS, SETTING, METHODS From the two most recent GWASs specifically centered on birth weight, which included 406 063 individuals and 423 683 individuals (63 365 trios) respectively, we identified genetic variants associated with fetal genetically determined birth weight, while adjusting for maternal genetic effects. We identified genetic variants associated with childhood BMI from an independent GWAS involving 21 309 European participants. On this basis, we employed two-sample MR techniques to examine the possible causal effects of fetal genetically determined birth weight on puberty timing using a large-scale GWAS of puberty timing (including 179 117 females of European ancestry). Furthermore, we employed advanced analytical methods, specifically MR mediation and MR-Cluster, to enhance our comprehension of the causal relationship between birth weight determined by fetal genetics and the timing of puberty. We also explored the pathways through which childhood BMI might act as a mediator in this relationship. MAIN RESULTS AND THE ROLE OF CHANCE In the univariable MR analysis, a one SD decrease in fetal genetically determined birth weight (∼ 418 g) was associated with a 0.16 (95% CI [0.07–0.26]) years earlier onset of puberty. The multivariable MR analysis including fetal genetically determined birth weight and childhood BMI in relation to puberty timing provided compelling evidence that birth weight had a direct influence on the timing of puberty. Lower birth weight (one SD) was associated with an earlier onset of puberty, with a difference of 0.23 (95% CI [0.05–0.42]) years. We found little evidence to support a mediating role of childhood BMI between birth weight and puberty timing (−0.07 years, 95% CI [−0.20 to 0.06]). LIMITATIONS, REASONS FOR CAUTION Our data came from European ancestry populations, which may restrict the generalizability of our results to other populations. Moreover, our analysis could not investigate potential non-linear relationships between birth weight and puberty timing due to limitations in genetic summary data. WIDER IMPLICATIONS OF THE FINDINGS Findings from this study suggested that low birth weight, determined by the fetal genome, contributes to early puberty, and offered supporting evidence to enhance comprehension of the fetal origins of disease hypothesis. STUDY FUNDING/COMPETING INTEREST(S) C.Z. was funded by the Sichuan Province Science and Technology Program [grant number 2021JDR0189]. J.Z. was supported by grants from the National Natural Science Foundation of China [grant number 82373588]. No other authors declare any sources of funding. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER N/A.

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胎儿基因决定的出生体重在青春期提前时间中起着因果作用：来自人类遗传学研究的证据

研究问题 胎儿的基因决定的出生体重与青春期的时间有关吗？摘要答案 基因决定的胎儿出生体重较低与青春期提前开始存在因果关系，与母亲宫内环境的间接影响无关。已知信息 之前的孟德尔随机化 (MR) 研究表明，出生体重、儿童期 BMI 和青春期开始之间存在潜在的因果关系。然而，他们没有区分通过胎儿基因组直接影响出生体重的遗传变异（称为胎儿遗传效应）和通过影响宫内环境间接影响出生体重的遗传变异（称为母体遗传效应）。必须强调的是，以前的研究是有限的，因为它们没有考虑到母体和胎儿遗传效应之间未解决的相关性所造成的潜在偏差。此外，胎儿基因组解释的出生体重变异比例远大于母体基因组解释的出生体重变异比例。研究设计、规模、持续时间我们使用来自欧洲血统个体的大规模全基因组关联研究 (GWAS) 的汇总数据进行了两个样本 MR 分析，以研究胎儿遗传决定的出生体重对青春期时间的因果影响。参与者/材料、设置、方法 从最近两次专门针对出生体重的 GWAS（分别包括 406 063 名个体和 423 683 名个体（63 365 个三人组））中，我们确定了与胎儿遗传决定的出生体重相关的遗传变异，同时调整母体遗传效应。我们从一项涉及 21,309 名欧洲参与者的独立 GWAS 中发现了与儿童 BMI 相关的遗传变异。在此基础上，我们采用两样本 MR 技术，利用大规模青春期时序 GWAS（包括 179 117 名欧洲血统女性）来检验胎儿基因决定的出生体重对青春期时序可能存在的因果影响。此外，我们采用先进的分析方法，特别是 MR 介导和 MR-Cluster，来增强我们对胎儿遗传学决定的出生体重与青春期时间之间因果关系的理解。我们还探讨了儿童体重指数可能在这种关系中发挥中介作用的途径。主要结果和机会的作用 在单变量 MR 分析中，胎儿遗传决定的出生体重 (∼ 418 g) 减少 1 个 SD 与青春期提前 0.16 (95% CI [0.07–0.26]) 年相关。多变量 MR 分析（包括胎儿遗传决定的出生体重和与青春期时间相关的儿童体重指数）提供了令人信服的证据，表明出生体重对青春期时间有直接影响。较低的出生体重（1 个 SD）与青春期提前开始相关，差异为 0.23 (95% CI [0.05–0.42]) 年。我们发现几乎没有证据支持儿童期 BMI 在出生体重和青春期时间之间的中介作用（−0.07 岁，95% CI [−0.20 至 0.06]）。局限性和注意理由我们的数据来自欧洲血统人群，这可能会限制我们的结果对其他人群的普遍适用性。此外，由于遗传汇总数据的限制，我们的分析无法调查出生体重和青春期时间之间潜在的非线性关系。研究结果的更广泛意义 这项研究的结果表明，由胎儿基因组决定的低出生体重有助于青春期提前，并为增强对胎儿疾病起源假说的理解提供了支持证据。研究经费/竞争利益 CZ 得到了四川省科技计划的资助 [批准号 2021JDR0189]。JZ得到了国家自然科学基金项目的资助[批准号82373588]。没有其他作者声明任何资金来源。作者没有利益冲突。试用注册号 不适用。