Mediating effects of gastroesophageal reflux disease and smoking behavior on the relationship between depression and chronic obstructive pulmonary disease: Trans-ethnic Mendelian randomization study.

Background: This study seeks to elucidate the association between depression and the risk of chronic obstructive pulmonary disease (COPD) by Mendelian randomization (MR) analysis, motivated by prior observational studies indicating a potential link between these conditions.

Methods: Data from individuals of European (EUR) and East Asian (EAS) ancestries diagnosed with major depressive disorder (MDD) were selected for analysis. The primary method utilized was inverse variance weighted (IVW) method, supplemented by a series of sensitivity analyses and false discovery rate (FDR) corrections. Subsequently, multivariable and mediation MR analyses were conducted to assess the impact of potential confounders and their mediating effects.

Results: IVW revealed a significant causal relationship between MDD and COPD within EUR ancestry (OR 1.425, 95 % CI 1.243-1.633, P = 3.56 × 10, P = 2.14 × 10). Additionally, replication datasets provided consistent evidence for these causal associations. Multivariable and mediation MR analyses identified gastroesophageal reflux disease (GORD) as a complete mediator (mediation effect: 98.97 %, P = 1.38 × 10), while smoking initiation (SI) (26.30 %, 5.54 × 10), age of smoking initiation (ASI) (18.73 %, 0.019), and cigarettes per day (CPD) (18.72 %, 0.004) were identified as partial mediators of this causal relationship. No causal association was detected in EAS ancestry, nor was reverse analysis.

Conclusions: This study established a causal relationship between MDD and COPD risk in EUR ancestry, identifying GORD and smoking as pivotal mediators. Future research involving larger cohorts is essential to validate the generalizability of these findings across other ancestries.