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.

Keywords: Basal cell carcinoma; Cross-tissue TWAS; Drug targets; Susceptibility genes.

Fig. 1

Study design. TWAS transcriptome-wide association study, UTMOST unified test for molecular signatures, GWAS genome-wide association, GTEx Genotype-Tissues Expression Project, FDR false discovery rate, FUSION functional summary-based imputation, MAGMA multi-marker Analysis of GenoMic Annotation

Fig. 2

COJO analysis results of IGKC. The jointly significant genes were shown in green and the marginally associated genes were displayed in blue

Fig. 3

SMR results of causal associations between identified genes and BCC in skin tissue

Fig. 4

The results of colocalization analysis between FLACC1, TMEM184B genes and BCC in Skin_Not_Sun_Exposed_Suprapubic tissue. A FLACC1 in the discovery stage; B TMEM184B in the discovery stage; C FLACC1 in the replicated stage

Fig. 5

Venn diagram. UTMOST, FUSION, MAGMA, SMR and colocalization analyses identified 10 common significant genes (discovery stage) and 3 common significant genes (replicated stage) associated with BCC risk

Fig. 6

Single-cell type expression in BCC tissue. A The 12 cell clusters labeled and annotated using marker genes; B and C The expression of identified genes in each cell type

Fig. 7

GeneMANIA gene network. A AFF1 as the core; B CASP8 as the core; C CYBRD1 as the core; D FLACC1 as the core; E HSCB as the core; F HSD17B13 as the core; G MAFF as the core; H PLA2G6 as the core; I TMEM184B as the core; J TRAK2 as the core

Fig. 8

PPI network, GO and KEGG analyses

Fig. 9

Molecular docking analysis of CASP8 with AN-9 and amooranin. A AN-9; B Amooranin