Pulmonary-Intestinal Axis: Shared Genetic Basis and Mediating Factors Identified Through Multi-Omics Analysis

Area of Science:

• Genetics
• Pulmonology
• Gastroenterology

Background:

• Chronic obstructive pulmonary disease (COPD) is a systemic illness with frequent gastrointestinal (GI) comorbidities.
• The shared genetic underpinnings and mediating factors of COPD-GI comorbidity are not well understood.

Purpose of the Study:

• To investigate the shared genetic architecture between COPD and GI diseases.
• To identify pleiotropic genes and pathways involved in COPD-GI comorbidity.
• To assess the mediating role of smoking in this association.

Main Methods:

• Genome-wide association study (GWAS) summary statistics for COPD, 15 GI diseases, and smoking phenotypes were analyzed.
• Genetic correlation was estimated using LDSC and HDL.
• Multi-trait analysis of GWAS (MTAG), locus-to-gene mapping, eQTL, pQTL, and Mendelian randomization (MR) were employed.

Main Results:

• Significant genetic correlations were found between COPD and nine GI diseases.
• Six comorbidity-associated loci and 13 pleiotropic genes were identified, with APOE highlighted by proteomic data.
• Lipid metabolism pathways were enriched, and MR indicated causal links between COPD and GERD, IBS, appendicitis, and gastric ulcer, with reverse causality for diverticular disease. Smoking partially mediated effects on GERD, appendicitis, and gastric ulcer.

Conclusions:

• COPD and various GI disorders share a pleiotropic genetic basis, forming part of COPD's systemic comorbidity spectrum.
• Genomic evidence supports a pulmonary-intestinal axis involving lipid metabolism and smoking, offering potential targets for intervention.