Multi-ancestry genome-wide association meta-analysis of hepatocellular carcinoma identifies eight risk loci including MAP3K9, DHRS1, MTTP, and 8q24.21
Chinaka, Ifechukwuamaka Schofield, Annabelle Amos, Christopher I Roberts, Lewis R Chen, Vincent L Han, Younghun Hassan, Manal Shetty, Shishir Mann, Jake P
Chinaka, Ifechukwuamaka
Schofield, Annabelle
Amos, Christopher I
Roberts, Lewis R
Chen, Vincent L
Han, Younghun
Hassan, Manal
Shetty, Shishir
Mann, Jake P
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death globally, often arising on a background of cirrhosis. Here, we aimed to establish genetic drivers of all-cause HCC across ancestries in a large meta-analysis. We included 15 cohorts comprising 17,697 HCC cases and 2,715,683 controls in this meta-analysis. We found 15 genome-wide significant (P < 5x10) germline loci, including in/near GCKR, MTTP, ADH5, 8q24.21 (nearest gene MYC), MAP3K9, and GABPB2, and a further two loci found on transcriptome- and regulome-wide association analyses. MAP3K9, TERT, and GABPB2 variants act independently of cirrhosis on both co-localisation analysis and sensitivity analyses. There was significant ancestral heterogeneity in 6 loci including variants in the HLA locus that had divergent effects on HCC risk between East Asian and European ancestries. Fine-mapping identified 11 potentially causal coding variants, including p.Leu446Pro in GCKR and p.Asp423Glu in MEN1. MEN1, 8q24.21 (nearest gene MYC), and TERT are all involved in the beta-catenin pathway transactivation complex. Transcriptome-wide analysis identified enrichment of germline-encoded DHRS1 in HCC. Regulome-wide analysis replicated the germline signal for EPHA2 and found a chromatin accessible region containing genes ZNF367 and HABP4. Finally, we demonstrated that population-level genetic architecture for HCC overlaps with steatotic and viral liver disease, and individuals with genetic risk for lower BMI have higher risk of HCC. Genetic risk for HCC is determined by germline susceptibility to beta-catenin pathway activation and cirrhosis. HCC is driven by both heterogenous and homogenous genetic factors across ancestries.
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Date
2026-06-25
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Article
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Citation
Chinaka I, Schofield A, Amos CI, Roberts LR, Chen VL, Han Y, Hassan M, Shetty S, Mann JP. Multi-ancestry genome-wide association meta-analysis of hepatocellular carcinoma identifies eight risk loci including MAP3K9, DHRS1, MTTP, and 8q24.21. HGG Adv. 2026 Jun 25:100639. doi: 10.1016/j.xhgg.2026.100639. Epub ahead of print.