Deciphering the Genetic Architecture of Chronic Obstructive Pulmonary Disease (COPD): Insights from the UK Biobank and Mendelian Randomization Analysis

Abstract Genetic susceptibility plays a crucial role in the development of Chronic Obstructive Pulmonary Disease (COPD), however, the research on genetic susceptibility genes for COPD is currently limited by incomplete understanding and insufficient identification of all contributory genetic factors. To address this issue, we conducted a prospective analysis in the UK Biobank study and Mendelian randomization (MR) analysis to unveil the causal relationship of potential genetic factors in COPD. Our findings underscore the involvement of key genes NME3, MPZL3, GNAQ, and ARL5B in COPD occurrence. Notably, the presence of the NME3 (0.998 ;0.997 −0.999; P = 0.004) and MPZL3 (0.999 ;0.998 −1.000; P = 0.048) potentially confers a reduced risk of COPD, while GNAQ (1.002 ;1.001 −1.004; P = 0.010) and ARL5B (1.004 ;1.000 −1.008; P = 0.040) are associated with an elevated risk of COPD. Multi-omics analysis showed that the expression levels of these key genes were highly correlated, either positively or negatively, with various COPD-related immune cell infiltrations, immune factor expression levels (immunomodulators, chemokines, and cellular receptors), and expression levels of disease genes associated with COPD. Additionally, we analyzed the expression levels of these key genes at the single-cell level, their involved signaling pathways, and regulatory networks to preliminarily reveal their potential molecular mechanisms in regulating COPD. Finally, potential drugs for treating COPD, such as Fostamatinib, MEK1-2-inhibitor, QL-XI-92, TWS-119, and VER-155008, were identified through drug targeting predictions using the Connectivity Map database.