Genetic overlap between impaired lung function and cardiovascular diseases revealed by a large-scale genome-wide cross-trait analysis

Abstract Background Increasing evidence have highlighted the phenotypic association between impaired lung function and cardiovascular diseases (CVD), but underlying shared genetic basis contributing to this association remain largely unexplored. Methods Utilizing summary data from the large-scale genome-wide association studies, our investigation delved into several aspects: the global and local genetic correlations, pleiotropic loci, and causal association between lung function and three prevalent CVD, namely coronary artery disease (CAD), heart failure (HF), and stroke. Results Our findings revealed significantly negative genetic correlations between lung function and CAD (rg = -0.20 to -0.17), HF (rg = -0.18 to -0.17), and stroke (rg = -0.17 to -0.16). After separating the whole genome into 2,353 independent regions, we determined 13, 4, and 3 significant regions for CAD, HF, and stroke with lung function, respectively. Furthermore, the global and local shared genetic basis were confirmed by the identification of multiple pleiotropic loci and multiple shared gene–tissue pairs. The pleiotropic loci were largely enriched in brain-related tissues, while shared gene-tissue pairs exhibited significant enrichment across nervous, cardiovascular, digestive, endocrine/exocrine, and respiratory systems. Mendelian randomization analysis demonstrated a significant causal association of genetically predicted lung function with CAD [OR (odds ratio) = 0.69 to 0.72] and stroke (OR = 0.81 to 0.90) but not with HF. No evidence of reverse causality was found. Conclusions These findings comprehensively uncover a shared genetic architecture as well as a causal association between impaired lung function and CVD, emphasizing the opportunity to enhance the quality of existing intervention strategies.