A cross-tissue transcriptome-wide association study identifies novel susceptibility genes for lung cancer in Chinese populations

Abstract

Abstract 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 × 10−5, PLung = 2.89 × 10−5), CBL (Pcross-tissue = 5.08 × 10−7, PLung = 1.82 × 10−4), ATR (Pcross-tissue = 1.45 × 10−5, PLung = 9.68 × 10−5), GYPE (Pcross-tissue = 1.45 × 10−5, PLung = 2.17 × 10−3) and PARD3 (Pcross-tissue = 5.79 × 10−6, PLung = 4.05 × 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, PGWAS = 5.54 × 10−5) and 11q23.3 (OR = 1.08, 95%CI: 1.04–1.13, PGWAS = 5.55 × 10−5), as well as the expression of DCAF16 (βGTEx = 0.24, PGTEx = 9.81 × 10−15; βNJLCC = 0.29, PNJLCC = 3.84 × 10−8) and CBL (βGTEx = −0.17, PGTEx = 2.82 × 10−8; βNJLCC = −0.32, PNJLCC = 2.61 × 10−7) in lung tissue. Functional annotations and phenotype assays supported the carcinogenic effect of these novel susceptibility genes in lung carcinogenesis.