Multi-ancestry genome-wide association meta-analysis of hepatocellular carcinoma identifies 15 risk loci including MAP3K9, DHRS1, MTTP, and 8q24.21.
Ifechukwuamaka Chinaka, Annabelle Schofield, Christopher I Amos et al.
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In 30 seconds
This multi-ancestry genome-wide association meta-analysis examined germline susceptibility to all-cause hepatocellular carcinoma (HCC) across 15 cohorts, including 17,697 affected individuals and 2,715,683 controls. It identified 15 genome-wide significant risk loci, including MAP3K9, MTTP, and 8q24.21 near MYC, plus two additional loci in transcriptome- and regulome-wide analyses. MAP3K9, TERT, and GABPB2 signals were independent of cirrhosis in the reported analyses. Genetic effects varied by ancestry at six loci, including HLA, while other risk factors were shared across ancestries.
Key findings
- The meta-analysis identified 15 genome-wide significant germline loci (p < 5 × 10 -8 ) and two further loci through transcriptome- and regulome-wide analyses.
- MAP3K9, TERT, and GABPB2 variants showed evidence of association with HCC independent of cirrhosis.
- Six loci showed significant ancestral heterogeneity; HLA variants had divergent HCC-risk effects between East Asian and European ancestries.
- Fine mapping identified 11 potentially causal coding variants, including variants in GCKR and MEN1.
Why it matters
The findings broaden understanding of inherited HCC susceptibility across ancestries and point to both shared and ancestry-dependent genetic contributions. Associations independent of cirrhosis suggest that some germline risk may relate to pathways beyond cirrhosis, while links to β-catenin pathway activation and liver-disease genetic architecture provide directions for further research.
What to keep in mind
The abstract does not report effect sizes for individual loci, limiting assessment of the magnitude of their associations.