Department of Epidemiology and Health Statistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
Department of Paediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Paediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Hum Reprod. 2024 Apr 3;39(4):792-800. doi: 10.1093/humrep/deae019.
Does fetal genetically determined birth weight associate with the timing of puberty?
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.
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.
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.
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.
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胎儿遗传决定的出生体重是否与青春期开始的时间有关？
较低的胎儿遗传决定的出生体重与青春期提前发生有关，这与母体宫内环境的间接影响无关。
先前的孟德尔随机化（MR）研究表明，出生体重、儿童时期 BMI 和青春期开始之间可能存在潜在的因果关系。然而，它们并没有区分直接通过胎儿基因组（称为胎儿遗传效应）影响出生体重的遗传变异，以及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，以前的研究受到限制，因为它们没有考虑到母体和胎儿遗传效应之间潜在的关联所带来的偏差。此外，由胎儿基因组解释的出生体重变化比例明显大于由母体基因组解释的比例。
研究设计、规模、持续时间：我们进行了两样本 MR 分析，使用欧洲血统个体的大规模全基因组关联研究（GWAS）的汇总数据，研究胎儿遗传决定的出生体重对青春期开始时间的因果影响。
参与者/材料、设置、方法：我们从两个专门针对出生体重的最新 GWAS 中确定了与胎儿遗传决定的出生体重相关的遗传变异，同时调整了母体遗传效应。我们从一个包含 21309 名欧洲参与者的独立 GWAS 中确定了与儿童时期 BMI 相关的遗传变异。在此基础上，我们采用两样本 MR 技术，使用大规模的青春期开始时间 GWAS（包括 179117 名欧洲血统女性），研究胎儿遗传决定的出生体重对青春期开始时间的可能因果影响。此外，我们采用了先进的分析方法，特别是 MR 中介和 MR-Cluster，以增强我们对胎儿遗传决定的出生体重与青春期开始时间之间因果关系的理解。我们还探讨了儿童时期 BMI 可能在这种关系中充当中介的途径。
在单变量 MR 分析中，胎儿遗传决定的出生体重降低一个标准差（约 418g）与青春期提前 0.16 年（95%CI [0.07-0.26]）有关。包括胎儿遗传决定的出生体重和儿童时期 BMI 与青春期开始时间的多变量 MR 分析提供了令人信服的证据，表明出生体重对青春期开始时间有直接影响。较低的出生体重（一个标准差）与青春期提前有关，差异为 0.23 年（95%CI [0.05-0.42]）。我们发现几乎没有证据支持儿童时期 BMI 在出生体重和青春期开始时间之间发挥中介作用（-0.07 年，95%CI [-0.20 至 0.06]）。
局限性、谨慎的原因：我们的数据来自欧洲血统人群，这可能限制了我们的研究结果在其他人群中的普遍性。此外，由于遗传汇总数据的限制，我们的分析无法研究出生体重和青春期开始时间之间潜在的非线性关系。
这项研究的结果表明，由胎儿基因组决定的低出生体重导致青春期提前，为增强对疾病起源于胎儿的假说的理解提供了支持证据。
研究资金/利益冲突：C.Z. 得到了四川省科技计划的资助[资助编号 2021JDR0189]。J.Z. 得到了国家自然科学基金的支持[资助编号 82373588]。其他作者没有声明任何资金来源。作者没有利益冲突。
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