: Recent genome-wide association studies (GWASs) have suggested several susceptibility loci of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) by statistical analysis at individual single-nucleotide polymorphisms (SNPs). However, these loci only explain a small fraction of HBV-related HCC heritability. In the present study, we aimed to identify additional susceptibility loci of HBV-related HCC using advanced knowledge-based analysis. Methods: We performed knowledge-based analysis

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... (including gene-and gene-set-based association tests) on variant-level association p-values from two existing GWASs of HBV-related HCC. Five different types of gene-sets were collected for the association analysis. A number of SNPs within the gene prioritized by the knowledge-based association tests were selected to replicate genetic associations in an independent sample of 965 cases and 923 controls. Results: The gene-based association analysis detected four genes significantly or suggestively associated with HBV-related HCC risk: SLC39A8, GOLGA8M, SMIM31, and WHAMMP2. The gene-setbased association analysis prioritized two promising gene set for HCC, cell cycle G1/S transition and NOTCH1 intracellular domain regulates transcription. Within the gene sets, three promising candidate genes (CDC45, NCOR1 and KAT2A) were further prioritized for HCC. Among genes of liver-specific expression, multiple genes previously implicated in HCC were also highlighted. However, probably due to small sample size, none of the genes prioritized by the knowledge-based association analyses are successfully replicated in the independent sample. Conclusions: This comprehensive knowledge-based association mining study suggested several promising genes and gene-sets associated with HBV-related HCC risks, which facilitate follow-up functional studies on the pathogenic mechanism of HCC. Background Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. With 750,000 new HCC cases diagnosed each year, it is the third leading cause of cancer mortality [1] . As many as 30% of patients diagnosed with hepatitis, fibrosis or cirrhosis ultimately develop HCC. In high endemic areas such as Africa and Asia, at least 60% of HCC is associated with hepatitis B virus (HBV) [2] .