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

Abstract

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 (N_cases = 56,167) and GERD (N_cases = 71,522). In addition, we generated instrumental variables for AD from the latest population-level genome-wide association study meta-analysis (N_cases = 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 European-ancestry 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.

Keywords: causal pathways; epidemiological approach; human genetics; risk factors.

Figure 1.

The work flow of instrumental variable analysis to estimate a potential causal effect of a modifiable exposure on a risk outcome. GWAS = genome-wide association study; IVW = inverse variance weighted; MR = Mendelian randomization.

Figure 2.

Causal relationships between asthma and AD. The inverse variance–weighted method was used to estimate the magnitude and direction of effect sizes, presented as ORs and 95% CIs. AD = atopic dermatitis; CI = confidence interval; OR = odds ratios.

Figure 3.

Causal relationships between GERD and atopic disorders (asthma or AD). The inverse variance–weighted method was used to estimate the magnitude and direction of effect sizes, presented as ORs and 95% CIs. AD = atopic dermatitis; CI = confidence interval; GERD = gastroesophageal reflux disease; OR = odds ratios.