Abstract
BACKGROUND: Lung cancer (LCA) and type 2 diabetes (T2D) are major global health burdens, with accumulating evidence suggesting a genomic link. This study systematically investigates the shared genetic architecture between LCA subtypes [small cell lung cancer (SCLC), lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD)] and T2D using large-scale genome-wide association studies (GWAS). METHODS: We conducted genome-wide genetic correlation analyses using linkage disequilibrium score regression (LDSC) and local genetic correlation analyses via heritability estimation from summary statistics (HESS). Pleiotropic variants were identified using the pleiotropic analysis under composite null hypothesis (PLACO), and functional annotation was performed with functional mapping and annotation of genetic associations (FUMA). Pathway and Gene Ontology (GO) analyses were carried out using Kyoto Encyclopedia of Genes and Genomes (KEGG) and GO, and tissue-specific enrichment patterns were evaluated with LDSC for the specific expression of genes analysis (LDSC-SEG). RESULTS: Our analysis revealed significant positive genetic correlations between T2D and LCA subtypes, particularly in SCLC and LUSC. Genome-wide genetic correlation analyses indicated the strongest correlation between LCA and T2D. Local genetic correlation analysis identified several genomic regions with suggestive significance. A total of 50 independent genomic risk loci were identified as pleiotropic loci, involving 34 unique chromosomal regions. Notably, the 9p21.3 region (CDKN2B-AS1) was identified in all pairwise trait analyses. Functional annotation highlighted deleterious variants in genes such as PROX1-AS1, BPTF, APOE, APOC1, TOMM40, TCF7L2, and PVRL2. Pathway analyses indicated significant enrichment in chromatin organization and metabolic regulation. CONCLUSIONS: This study provides robust evidence of a shared genetic architecture between LCA subtypes and T2D, highlighting potential therapeutic targets. Future research should focus on validating these findings in larger cohorts and exploring the functional roles of the identified genes in the co-occurrence of these conditions.