Causal association between frailty and chronic obstructive pulmonary disease: insights from bidirectional Mendelian randomization and mediation analysis

Abstract Background Observational studies have underscored a robust association between frailty and chronic obstructive pulmonary disease (COPD), yet the causality remains equivocal.Methods This study employed bidirectional two-sample Mendelian randomization (MR) analysis. Individuals of European ancestry with frailty and COPD were selected for analysis under the genome-wide significance threshold (P < 5×10–8). Univariable MR investigated the causal relationship between frailty and COPD. Genetic correlation was assessed using linkage disequilibrium score (LDSC) regression, while multivariable MR and mediation analysis explored the influence of various confounders and their mediating effects. The primary analytic approach was inverse variance weighted (IVW), supported by comprehensive sensitivity analyses.Results LDSC analysis revealed moderate genetic correlations between frailty and Global Biobank Meta-Analysis Initiative (GBMI) COPD (rg = 0.643, P = 6.66 × 10 − 62) as well as FinnGen COPD (rg = 0.457, P = 8.20 × 10 − 28). IVW analysis demonstrated that frailty was associated with increased risk of COPD in both the GBMI cohort (OR, 1.784; 95% CI, 1.475 to 2.158; P = 2.40 × 10 − 9) and the FinnGen database (OR, 1.854; 95% CI, 1.411 to 2.434; P = 9.02 × 10 − 6). Concurrently, COPD was identified as a susceptibility factor for frailty (GBMI: β, 0.104; 95% CI, 0.058 to 0.151; P = 1.25 × 10 − 5; FinnGen: β, 0.050; 95% CI, 0.020 to 0.079; P = 9.22 × 10 − 4). These consistent findings persisted after adjustment for potential confounders such as body mass index, age of smoking initiation, smoking initiation and sarcopenia-related traits in multivariable analyses. Additionally, mediation analysis revealed that walking pace mediated 19.11% (95% CI, 7.17–31.05%) and 15.40% (95% CI, 2.82–27.98%) of the impact of frailty on COPD risk, and 17.58% (95% CI, 2.63–32.53%) and 23.26% (95% CI, 0.97–45.55%) of the effect of COPD on frailty risk in the GBMI and FinnGen cohorts, respectively.Conclusions This study has strengthened the current evidence affirming a reciprocal causal relationship between frailty and COPD, highlighting walking pace as a pivotal mediator. Future larger-scale research is warranted to ascertain the applicability of these findings across diverse ancestries.