Genetic Architecture of Comorbidity Between Chronic Obstructive Pulmonary Disease and Cardiovascular Diseases: Exploring Shared Mechanisms and Potential Therapeutic Targets

Background: Chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVDs), including hypertension (HTN), coronary heart disease (CHD), and heart failure (HF), are major global health burdens. The shared genetic mechanisms underlying the high comorbidity between COPD and CVDs remain unclear. Methods: We integrated large-scale GWAS summary statistics for COPD and three major CVDs (HTN, CHD, HF). Several analytic approaches were applied, including linkage disequilibrium score regression (LDSC), high-definition likelihood (HDL), multi-marker analysis of genomic annotation (MAGMA), pleiotropic analysis under composite null hypothesis (PLACO), and summary-data-based Mendelian randomization (SMR). These methods were used to evaluate genetic correlations, identify shared risk loci, and prioritize potential therapeutic targets. Results: LDSC and HDL analyses revealed significant positive genetic correlations between COPD and the three CVDs (rg = 0.23-0.38, P < 0.05). MAGMA enrichment analysis identified 277 unique pleiotropic genes enriched in pathways such as Notch signaling and nicotinic acetylcholine receptor signaling. Tissue-specific analyses indicated that shared genetic signals were enriched not only in the lung and heart but also in neuroendocrine-related tissues such as the cerebellum and pituitary, suggesting the involvement of a potential "lung-heart-brain" multi-organ axis. PLACO identified 94 pleiotropic SNPs, with consistent colocalization signals at 15q25.1 (CHRNA3/5, IREB2) and 4q22 (SOX7). SMR analysis further prioritized 626 candidate genes, including ZNF652, XRCC3, SLC22A5, and SOX7, which may serve as potential therapeutic targets. Conclusion: This study provides genetic evidence for shared mechanisms linking COPD with HTN, CHD, and HF. It highlights the roles of neurotransmitter receptors, iron metabolism, vascular development, and energy metabolism in COPD-CVD comorbidity. These findings offer insights into precision prevention and therapeutic strategies targeting COPD-CVD comorbidity.