Observational studies showed an inverse association between birth weight and chronic kidney disease (CKD) in adulthood existed. However, whether such an association is causal remains fully elusive. Moreover, none of prior studies distinguished the direct fetal effect from the indirect maternal effect. Herein, we aimed to investigate the causal relationship between birth weight and CKD and to understand the relative fetal and maternal contributions. Meta-analysis (n = ~22 million) showed that low birth weight led to ~83% (95% confidence interval [CI] 37–146%) higher risk of CKD in late life. With summary statistics from large scale GWASs (n = ~300 000 for birth weight and ~481 000 for CKD), linkage disequilibrium score regression demonstrated birth weight had a negative maternal, but not fetal, genetic correlation with CKD and several other kidney-function related phenotypes. Furthermore, with multiple instruments of birth weight, Mendelian randomization showed there existed a negative fetal casual association (OR = 1.10, 95% CI 1.01–1.16) between birth weight and CKD; a negative but non-significant maternal casual association (OR = 1.09, 95% CI 0.98–1.21) was also identified. Those associations were robust against various sensitivity analyses. However, no maternal/fetal casual effects of birth weight were significant for other kidney-function related phenotypes. Overall, our study confirmed the inverse association between birth weight and CKD observed in prior studies, and further revealed the shared maternal genetic foundation between low birth weight and CKD, and the direct fetal and indirect maternal causal effects of birth weight may commonly drive this negative relationship.

中文翻译：

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出生体重与慢性肾病的关系：来自系统学回顾和两样本孟德尔随机化分析的证据。

观察性研究表明，出生体重与成年期慢性肾病 (CKD) 之间存在负相关。然而，这种关联是否是因果关系仍然完全难以捉摸。此外，之前的研究都没有将直接胎儿效应与间接母体效应区分开来。在此，我们旨在调查出生体重与 CKD 之间的因果关系，并了解胎儿和母体的相对贡献。荟萃分析（n  = ~2200 万）表明，低出生体重导致晚年 CKD 风险增加 ~83%（95% 置信区间 [CI] 37-146%）。来自大规模 GWAS 的汇总统计数据 ( n = ~300 000 出生体重和 ~481 000 CKD），连锁不平衡评分回归表明出生体重与 CKD 和其他几种肾功能相关表型与母体（而非胎儿）遗传相关性呈负相关。此外，使用多种出生体重工具，孟德尔随机化显示出生体重与 CKD 之间存在负胎儿偶然关联（OR = 1.10，95% CI 1.01–1.16）；还确定了一个负面但不显着的母亲偶然关联（OR = 1.09，95% CI 0.98–1.21）。这些关联在各种敏感性分析中都是稳健的。然而，对于其他肾功能相关表型，出生体重对母体/胎儿的偶然影响不显着。总体而言，我们的研究证实了先前研究中观察到的出生体重与 CKD 之间的负相关，