Integrating Lung Tissue-based Transcriptome-Wide Association Study with Single-cell RNA-sequencing Uncovers Susceptibility Genes and Cell Types Underlying Lung Cancer Risk

Genome-wide association studies (GWASs) have identified approximately 100 loci for lung cancer, but potential causal genes remain largely unknown. To address this, we conducted a lung tissue-specific transcriptome-wide association study (TWAS). Gene expression prediction models were constructed using data of adjacent normal lung tissues from our Vanderbilt Thoracic Biorepository (N=314) and normal lung tissues from the GTEx (N=466) and then applied to our lung cancer GWAS meta-analysis (55,174 cases and 1,294,174 controls). We identified 109 unique risk genes for lung cancer and its histological subtypes. Of them, 71 unique genes were novel discoveries, and 13 unique genes reside in novel loci. Smoking-conditional analysis revealed that 52 unique genes are unrelated to smoking behavior. Seven unique genes showed cell-type-specific colocalization within potential risk cell types, including the alveolar type I and II, dendritic, and natural killer cells. Seventeen unique genes are targeted of 58 drugs that have been approved or in Phase II or III trials. In addition, 22 unique potential causal genes were supported by both Mendelian randomization and colocalization. Functional validation identified three genes through in vitro knockdown experiments. Our study identified new lung cancer candidate risk genes and offered insights into lung cancer biology and future translational utilities.