Fetal genetically determined birth weight plays a causal role in earlier puberty timing: evidence from human genetic studies.

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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. 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. 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]). 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. 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. N/A.