Transcriptome- and methylome-wide association studies prioritized lung cancer genes in East Asian populations

The relationship between gene expression, DNA methylation, and lung cancer remains elusive in East Asian (EAS) populations. Transcriptome- and methylome-wide association studies (TWAS/MWAS) help uncover gene-trait associations by integrating multi-omics data, yet models trained mainly on European references limit cross-population generalizability. To address this, we developed EAS-specific gene expression and DNA methylation prediction models using whole-blood data from over 800 and 4,300 individuals, respectively. Applying these to lung cancer GWAS from Nanjing Medical University (13,327 cases; 13,328 controls) and Biobank Japan (4,444 cases; 489,012 controls), we identified 25 genes and 42 CpGs associated with lung cancer risk in the discovery stage, with seven genes and 32 CpGs replicated. Three novel genes outside known GWAS loci-RP11-57K17.1 (6q22.31), RP11-313J2.1 (10q11.21), and BMS1P2 (10q11.22)-were identified. In addition, Mendelian randomization analyses suggested that methylation-mediated downregulation of RP11-147L13.11 can reduce lung cancer risk. Our study reveals new susceptibility genes and offers insights into genetic-epigenetic regulatory mechanisms in lung cancer among EAS populations.