Transcriptome-wide association study for persistent hepatitis B virus infection and related hepatocellular carcinoma

Area of Science:

• Genetics
• Hepatology
• Immunology

Background:

• Genome-wide association studies (GWAS) have identified genetic variants for persistent hepatitis B virus (HBV) infection, but many lie in noncoding regions, obscuring causal genes.
• Understanding the genetic basis of persistent HBV infection is crucial for developing targeted therapies and preventative strategies.

Purpose of the Study:

• To identify novel genes and causal variants associated with persistent HBV infection using a transcriptome-wide association study (TWAS) approach.
• To investigate the association of identified variants with the risk of HBV-related hepatocellular carcinoma (HCC).

Main Methods:

• Integrated RNA sequencing and genotyping data from GTEx with GWAS data for TWAS.
• Screened cis-heritable genes and predicted genetic expression using GCTA and GEMMA.
• Conducted eQTL-based stepwise logistic regression and validated findings in independent cohorts for HBV infection and HBV-related HCC.

Main Results:

• Identified seven genes associated with HBV infection, including novel loci BAK1, HLA-DOB, C4A, PARP9, and TMEM191A, alongside previously reported HLA-DPA1 and HLA-DPB1.
• Discovered eight variants independently associated with persistent HBV infection.
• Two single nucleotide polymorphisms (SNPs), rs9272714 and rs9394194, were significantly associated with HBV-related HCC risk.

Conclusions:

• This study successfully integrated transcriptome and genetic data to identify novel susceptibility genes and variants for persistent HBV infection.
• The findings provide insights into the genetic etiology of persistent HBV infection and its progression to HBV-related HCC, highlighting immune-related genes.
• Identified potential target genes and causal variants, offering a foundation for future research and therapeutic interventions.