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.Author summary: This study leveraged large-scale blood multi-omics datasets to conduct comprehensive data mining and analysis for lung cancer in East Asian (EAS) populations. Using two-stage transcriptome- and methylome-wide association analyses (TWAS/MWAS), this study screened and validated 7 genes and 32 CpG sites associated with lung cancer risk, including three newly found genes. Subsequent colocalization and Mendelian randomization analyses revealed key epigenetic regulatory pathways. Specifically, two methylation markers were found to regulate the lncRNA RP11-147L13.11 and ultimately affect lung cancer susceptibility. This data-driven work uncovers population-specific molecular markers and regulatory mechanisms, offering solid clues for further research on the onset and progression of lung cancer among East Asians.