Multi-trait association analysis reveals shared genetic architecture between lung cancer and cardiometabolic diseases

Lung cancer (LC) frequently coexists with cardiometabolic diseases (CMDs), complicating clinical management, but their shared genetic architecture remains largely unknown. Here, we analyzed genome-wide association study (GWAS) statistics for LC and 36 cardiometabolic traits and diseases (CMTs) to determine genetic correlations and shared biological pathways. We further explored underlying mechanisms through the analysis of bulk and single-cell RNA sequencing data and identified potential therapeutic candidates using drug-gene interaction databases. Significant genetic associations were revealed between LC and 16 CMTs, including subarachnoid hemorrhage, peripheral arterial disease, heart failure, and physiological traits (Padj <0.05). The shared genes were identified as enriched in lipid and cholesterol metabolism. Notably, monocyte-derived macrophages (mo-Macs) in lung adenocarcinoma exhibited M2-like polarization under high cholesterol metabolism and rosuvastatin and lovastatin were identified as potential drugs for LC-CMD comorbidities. Our findings demonstrate a role for cholesterol metabolism in LC-CMD comorbidities, offering insights into the underlying mechanisms and potential therapeutic strategies.