Unveiling the genetic overlap and causal links between gastroesophageal reflux disease and asthma

Background: Gastroesophageal reflux disease (GERD) and asthma are commonly co-occurring conditions, with shared genetic factors identified. However, the specific loci and the influence of common genetic architecture remain undefined. Methods: We obtained genome-wide association study (GWAS) summary statistics for GERD (71 522 cases and 261 079 controls) and asthma (56 167 cases and 352 255 controls). Using linkage disequilibrium score regression (LDSC), we assessed genetic correlations between GERD and asthma. Bidirectional Mendelian randomization (MR) was performed to investigate potential causal relationships, followed by cross-trait GWAS meta-analysis and colocalization analysis to identify shared risk loci. Additionally, summary-data-based MR and transcriptome-wide association study were conducted to pinpoint common functional genes. Finally, we analyzed gene expression profiles in both healthy individuals and GERD patients using esophageal single-cell RNA sequencing (scRNA-seq) data. Results: We identified a significant genetic correlation between GERD and asthma ( r g = 0.37, P = 6.19 × 10 –38 ) and a significant causal effect of GERD on asthma [odds ratio (OR) = 1.22, P = 1.54 × 10 −5 ]. Cross-trait meta-analyses revealed 56 shared risk loci between GERD and asthma, including 51 loci that were newly identified. Three loci (rs61937247, rs7960225, and rs769670) exhibited evidence of colocalization. Gene-level analyses pinpointed three novel shared genes ( RBM6, SUOX , and MPHOSPH9 ) between GERD and asthma. scRNA-seq analysis uncovered heightened expression of these genes in immune cells of patients diagnosed with GERD. Conclusion: Our study has discovered novel shared genetic loci and candidate genes between GERD and asthma, providing further insights into the genetic susceptibility of comorbidity and potential mechanisms of the two diseases.