Abstract: Shiyu Chen,1,* Xiaojian Li,1,* Rongfang Xie1,2 1Clinical Medical College,Jiangxi University of Chinese Medicine, Nanchang, 330004, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, 330006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rongfang Xie, Clinical Medical College, Jiangxi University of Chinese Medicine, Nanchang, 330004, People’s Republic of China, Email 283700257@qq.comBackground: 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 ...
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