Unveiling novel susceptibility genes and drug targets for basal cell carcinoma by a cross-tissue transcriptome-wide association study

Abstract

Objective: To identify novel susceptibility genes and drug targets for basal cell carcinoma (BCC). Methods: We performed a transcriptome-wide association study (TWAS) to identified the susceptibility genes and potential drug targets for BCC. The cross-tissue TWAS was conducted to discover the candidate genes for BCC. Functional Summary-based Imputation (FUSION) analysis was used to validate these genes in the single tissues. Multimarker Analysis of Genomic Annotation (MAGMA) was employed to further screen candidate genes. Summary data-based Mendelian randomization (SMR) and colocalization analyses were applied to infer causal relationships between candidate genes and BCC. The expression pattern of the identified genes in single-cell types was also investigated. Function, pathway enrichment and disease connection analyses were performed to understand the biological implication of identified genes. Additionally, druggability of the identified genes was evaluated to discover potential candidate drugs for BCC. Results: Ninety-five genes were identified by cross-tissue TWAS analysis. Among them, 24 genes were confirmed by FUSION and MAGMA methods. Ten genes were further confirmed by SMR and colocalization analyses. Three genes were replicated by using another GWAS data. The potential interacting gene networks constructed with these identified genes were mainly involved in viral life cycle-HIV-1, GABAergic synapse, nicotine addiction, ether lipid metabolism, and mineral absorption pathways. AN-9 and amooranin might be candidate drugs for BCC. Conclusions: We have identified 10 susceptibility genes associated with BCC risk, which might deepen our comprehension of BCC pathogenesis and illuminating new avenues for therapeutic and preventive drug development.