Mendelian Randomization Analysis Reveals a Complex Genetic Interplay among Atopic Dermatitis, Asthma, and Gastroesophageal Reflux Disease

Rationale: Gastroesophageal reflux disease (GERD) is commonly associated with atopic disorders, but cause-effect relationships remain unclear. Objectives: We applied Mendelian randomization analysis to explore whether GERD is causally related to atopic disorders of the lung (asthma) and/or skin (atopic dermatitis [AD]). Methods: We conducted two-sample bidirectional Mendelian randomization to infer the magnitude and direction of causality between asthma and GERD, using summary statistics from the largest genome-wide association studies conducted on asthma (Ncases = 56,167) and GERD (Ncases = 71,522). In addition, we generated instrumental variables for AD from the latest populationlevel genome-wide association study meta-analysis (Ncases = 22,474) and assessed their fidelity and confidence of predicting the likely causal pathway(s) leading to asthma and/or GERD. Measurements and Main Results: Applying three different methods, each method revealed similar magnitude of causal estimates that were directionally consistent across the sensitivity analyses. Using an inverse variance-weighted method, the largest effect size was detected for asthma predisposition to AD (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.34-1.59), followed by AD to asthma (OR, 1.34; 95% CI, 1.24-1.45). A significant association was detected for genetically determined asthma on risk of GERD (OR, 1.06; 95% CI, 1.03-1.09) but not genetically determined AD on GERD. In contrast, GERD equally increased risks of asthma (OR, 1.21; 95% CI, 1.09-1.35) and AD (OR, 1.21; 95% CI, 1.07-1.37). Conclusions: This study uncovers previously unrecognized causal pathways that have clinical implications in Europeanancestry populations: 1) asthma is a causal risk for AD, and 2) the predisposition to AD, including asthma, can arise from specific pathogenic mechanisms manifested by GERD.