Genetic and Molecular Interconnections Between Chronic Obstructive Pulmonary Disease and Osteoporosis: Insights from Single-Cell and Mendelian Randomization Analyses.

Background: Chronic obstructive pulmonary disease (COPD) and osteoporosis are common comorbid conditions, both of which impose a significant health burden. This research employs single-cell data and Mendelian randomization analysis to pinpoint genes associated with both conditions and investigate their possible mechanistic links. Methods: Single-cell datasets pertaining to chronic obstructive pulmonary disease and osteoporosis were subjected to analysis to identify DEGs. Mendelian Randomization analysis was employed to prioritize key causal genes. Subsequent functional profiling encompassed the reconstruction of gene regulatory networks, evaluation of Chemical-disease associations, annotation of specific cell types, and development of pseudo-time trajectory models, along with immune cell infiltration analysis, molecular docking, and molecular dynamics simulations. Results: Single-cell analysis found 2,623 genes linked to chronic obstructive pulmonary disease and 2,454 to osteoporosis, with 161 genes upregulated and 106 downregulated in both. Mendelian randomization analysis identified PADI4 and TUBB2A as key regulators. The MAPK signaling pathway was a critical shared pathway. Molecular docking and molecular dynamics simulations revealed strong binding potential between BPA, TCDD, estradiol and the target proteins. NK cells were identified as a key cell type in COPD, and monocytes in osteoporosis. Pseudo-time analysis revealed distinct developmental trajectories for NK and monocyte subpopulations. Conclusion: This study identifies PADI4 and TUBB2A as potential genetic links between COPD and osteoporosis, and highlights BPA, TCDD, and estradiol as potential chemical factors, providing insights into their shared molecular mechanisms.