AUTHOR=Zhu Xiao-Bo , Hou Yu-Qing , Ye Xiang-Yu , Zou Yi-Xin , Xia Xue-Shan , Yang Sheng , Huang Peng , Yu Rong-Bin 

TITLE=Identifying and Exploring the Candidate Susceptibility Genes of Cirrhosis Using the Multi-Tissue Transcriptome-Wide Association Study

JOURNAL=Frontiers in Genetics

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.878607

DOI=10.3389/fgene.2022.878607

ISSN=1664-8021

ABSTRACT=Objective: We identify and explore the candidate susceptibility genes of cirrhosis and underlying biological mechanism. Methods: We downloaded the GWAS summary data of 901 cirrhosis cases and 451,363 controls and integrated it with reference models of five potential tissues from Genotype-Tissue Expression Project (GTEx), including whole blood, liver, pancreas, spleen, and thyroid, to identify genes whose predicted expression are associated with cirrhosis. We then downloaded gene expression data of individuals with hepatocellular carcinoma from the TCGA database to conduct differential expression analysis to verify these identified genes and explored their possible role in driving cirrhosis via functional enrichment and gene set enrichment analysis (GSEA). Results: We identified ten significant genes (SKIV2L, JPH4, UQCC2, RP11-91I8.3, MAU2, ERAP1, PUS3, ZNF677, ARHGAP40 and SHANK3) associating with cirrhosis at a Bonferroni-corrected threshold of P < 0.01, among which 2 (SKIV2L and JPH4) were identified in liver and 5 (SKIV2L, JPH4, MAU2, SHANK3 and UQCC2) were verified by differential expression analysis at a FDR-corrected threshold of P < 0.01. Enrichment analysis suggested that the degradation process of RNA which is enriched by 58 genes is significantly under-enriched in liver cancer tissues (P = 0.0268). Conclusion: We have identified several candidate genes for cirrhosis in multiple tissues and performed differential genetic analysis using the Liver Cancer Database to verify the significant genes. We found that the genes SKIV2L and JPH4 identified in liver are of particular concern. Finally, through enrichment analysis, we speculate that the process of mRNA transcription and RNA degradation may play a role in cirrhosis.