Gastroesophageal reflux disease and childhood asthma: A bidirectional two-sample Mendelian randomization study

Gastroesophageal reflux disease (GERD) commonly coexists with childhood asthma, but observational evidence is confounded by adiposity, medications, and shared environments, and reverse causation cannot be excluded. Mendelian randomization (MR), using germline variants as instruments, can mitigate confounding and reverse causation. We conducted a bidirectional two-sample MR to clarify whether genetically proxied GERD liability causally increases childhood asthma risk and whether childhood asthma liability influences GERD. Summary-level genome-wide association study (GWAS) data for gastroesophageal reflux and childhood asthma were obtained from the OpenGWAS repository, and both GWAS were conducted in individuals of European ancestry, so the causal estimates are mainly applicable to European populations. Instrumental variables were selected according to standard two-sample MR criteria. Bidirectional MR analyses were performed in R using the TwoSampleMR package. Of 5 complementary MR methods, inverse-variance weighting (IVW) was prespecified as the primary analysis. Heterogeneity was assessed with Cochran Q under IVW and MR-Egger models. Robustness was evaluated by leave-one-out analysis, Mendelian Randomization Pleiotropy RESidual Sum and Outlier, and the MR-Egger intercept (for directional pleiotropy). In the forward direction (gastroesophageal reflux → childhood asthma), IVW indicated increased risk (odds ratio = 1.792; 95% confidence interval, 1.661-1.933; P = 2.033 × 10-51 < .001). Results were consistent across the other 4 MR methods. There was no significant heterogeneity by Cochran Q, no evidence of directional pleiotropy by the MR-Egger intercept, no outliers by Mendelian Randomization Pleiotropy RESidual Sum and Outlier, and leave-one-out analysis supported stability. In the reverse direction (childhood asthma → gastroesophageal reflux), IVW showed no association (odds ratio = 1.029; 95% confidence interval, 0.983-1.078; P = .225 > .05), with concordant findings from the other MR methods and similarly negative sensitivity tests. Genetic evidence supports a positive causal effect of gastroesophageal reflux on the risk of childhood asthma, whereas childhood asthma does not appear to causally influence gastroesophageal reflux.