A Cross-Tissue Transcriptome-Wide Association Study Identifies Novel Susceptibility Genes For Lung Cancer In Chinese Populations

Although dozens of susceptibility loci have been identified for lung cancer in genome-wide association studies (GWASs), the susceptibility genes and underlying mechanisms remain unclear. In this study, we conducted a cross-tissue transcriptome-wide association study (TWAS) with UTMOST based on summary statistics from 13 327 lung cancer cases and 13 328 controls and the genetic-expression matrix over 44 human tissues in the Genotype-Tissue Expression (GTEx) project. After further evaluating the associations in each tissue, we revealed 6 susceptibility genes in known loci and identified 12 novel ones. Among those, five novel genes, including DCAF16 (Pcross-tissue = 2.57 x 10-5, P-Lung = 2.89 x 10(-5)), CBL (Pcross-tissue = 5.08 x 10(-7), P-Lung = 1.82 x 10(-4)), ATR (Pcross-tissue = 1.45 x 10(-5), P-Lung = 9.68 x 10(-5)), GYPE (Pcross-tissue = 1.45 x 10(-5), P-Lung = 2.17 x 10(-3)) and PARD3 (Pcross-tissue = 5.79 x 10(-6), P-Lung = 4.05 x 10(-3)), were significantly associated with the risk of lung cancer in both cross-tissue and lung tissue models. Further colocalization analysis indicated that rs7667864 (C > A) and rs2298650 (G > T) drove the GWAS association signals at 4p15.31-32 (OR = 1.09, 95%CI: 1.04-1.12, P-GWAS = 5.54 x 10(-5)) and 11q23.3 (OR = 1.08, 95%CI: 1.04-1.13, P-GWAS = 5.55 x 10(-5)), as well as the expression of DCAF16 (beta(GTEx) = 0.24, P-GTEx = 9.81 x 10(-15); beta(NJLCC) = 0.29, P-NJLCC = 3.84 x 10(-8)) and CBL (beta(GTEx) = -0.17, P-GTEx = 2.82 x 10(-8); beta(NJLCC) = -0.32, P-NJLCC = 2.61 x 10(-7)) in lung tissue. Functional annotations and phenotype assays supported the carcinogenic effect of these novel susceptibility genes in lung carcinogenesis.