Abstract: Background：Gestational diabetes mellitus (GDM) is one of the common metabolic disorders of pregnancy, and the hyperglycemia that occurs in the mother during pregnancy may affect the fetal immune system and lung development, leading to a greater susceptibility to asthma in children. However, in traditional epidemiologic cohort studies, the existing findings may be affected by confounding factors, and there is a need to further explore the causal association between GDM and childhood asthma and develop more effective prevention and management strategies. Objective：To investigate whether there is a causal association between gestational diabetes mellitus (GDM) and childhood asthma in offspring by using a two-sample Mendelian randomization (TSMR) subgroup, and to provide recommendations for clinical management. Design：Case-control study. Methods：Utilizing the most recent and largest sample size genome-wide association study (GWAS) summary data, we selected genetic loci closely related to GDM and childhood asthma, using single nucleotide polymorphisms (SNPs) as instrumental variables, GDM as the exposure factor and childhood asthma as the outcome variable, to analyze the causal relationship between GDM and childhood-onset asthma. A P value (P<5.0×10-7) was set for the screening of instrumental variables, and in order to avoid linkage disequilibrium (LD) bias, the LD of significant SNPs associated with GDM had to satisfy the conditions: r2<0.001 and a genetic distance of 10, 000 kb. SNPs with the F-statistics<10 were excluded. The inverse variance weighted(IVW) method, alongside weighted median and MR-Egger regression methods, were used for TSMR analysis to infer causality. Sensitivity analyses were performed in parallel using MR-Egger regression, Cochran's Q-test, and the "leave-one-out" method. Statistical analyses were performed using R 4.3.1 software package TwoSampleMR with a significance level of α=0.05. Main outcome measures：Association between GDM and childhood asthma. Results：In the Finnish GWAS summary data, the GDM dataset included 6,033 cases and 110,330 controls, totaling 16,379,684 SNPs. The asthma dataset included 3,025 cases and 135,449 controls, with a total of 16,379,865 SNPs. According to the screening criteria for research instrumental variables, 10 SNPs were selected as instrumental variables, all with F-statistics>10. IVW results indicated a causal relationship between GDM and increased risk of childhood asthma (OR=1.15, 95%CI: 1.01-1.32, P=0.039). Cochran's Q test showed no heterogeneity among the included SNPs (P> 0.05). MR-Egger regression's intercept was -0.013 (P=0.68), indicating a low likelihood of pleiotropic effects. Sensitivity analysis using the leave-one-out method did not reveal any SNPs with a strong influence on the results, suggesting stability in the causal relationship. Funnel plot analysis demonstrated that the causal effect of GDM on childhood asthma was symmetrically distributed when using individual SNPs as instrumental variables. Conclusion：There is a positive causal association between GDM and childhood-onset asthma.

Key words: Gestational diabetes mellitus, Childhood asthma, Mendelian randomization