Abstract
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a systemic condition with comorbidities beyond the lung (eg, cardiovascular and metabolic disorders), and gastrointestinal (GI) disorders are also common. The shared genetic basis of COPD-GI comorbidity and its mediating factors remain unclear. We hypothesized that COPD and GI diseases share pleiotropic genetic architecture implicating lipid-metabolic pathways, with smoking mediating part of the association. METHODS: We analyzed publicly available European-ancestry GWAS summary statistics for COPD (Global Biobank Meta-analysis Initiative), 15 GI diseases (FinnGen), and smoking phenotypes (UK Biobank). Genetic correlation was estimated using linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL). Multi-trait analysis of GWAS (MTAG) boosted COPD discovery by leveraging genetically correlated GI traits. We integrated locus-to-gene mapping with multi-tissue expression quantitative trait loci (eQTL) and plasma protein quantitative trait loci (pQTL) evidence to prioritize shared loci, genes, and proteins. Bidirectional two-sample Mendelian randomization (MR) tested causal directions, and two-step mediation MR evaluated smoking. RESULTS: COPD showed significant genetic correlation with nine GI diseases. We identified six comorbidity-associated loci (three with CADD > 12.37) and 13 unique candidate pleiotropic genes; APOE was supported by proteomic evidence. Enrichment analyses highlighted lipid-metabolism pathways. MR suggested COPD increases risk of gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), acute appendicitis, and gastric ulcer, while diverticular disease showed reverse causality toward COPD. Smoking partially mediated the COPD effect on GERD, acute appendicitis, and gastric ulcer. CONCLUSION: COPD and multiple GI disorders share a distributed pleiotropic genetic basis within the broader systemic comorbidity spectrum of COPD. Multi-omics evidence supports a genomic pulmonary-intestinal axis in which lipid metabolism and smoking-related mechanisms contribute to COPD and GI comorbidity, providing targets for risk stratification and potential intervention.