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. 2025 Jun 11;7(9):101485.
doi: 10.1016/j.jhepr.2025.101485. eCollection 2025 Sep.

Genome-wide meta-analysis identifies nine loci associated with higher risk of hepatocellular carcinoma development

Jonas Ghouse  1   2 , Helene Gellert-Kristensen  3 , Colm J O'Rourke  4 , Anne-Sofie Seidelin  3 , Gudmar Thorleifsson  5 , Gardar Sveinbjörnsson  5 , Vinicius Tragante  5 , Chigoziri Konkwo  6   7   8 , Joseph Brancale  6   7   8 , Silvia Vilarinho  6   7   8 , Tim M Eyrich  3 , Gustav Ahlberg  1   2 , Johan S Bundgaard  1 , Søren A Rand  1 , Pia R Lundegaard  2 , Erik Sørensen  9 , Christina Mikkelsen  9   10 , Jacob Træholt  9 , Christian Erikstrup  11 , Khoa M Dinh  11 , Mie T Bruun  12 , Bitten Aa Jensen  13 , Jakob T Bay  14 , Søren Brunak  15 , Karina Banasik  15   16 , Henrik Ullum  17 ; DBDS Genomic Consortium, Estonian Biobank Research Team; Triin Laisk  18 , Reedik Mägi  18 , Lincoln D Nadauld  19 , Kirk U Knowlton  19 , Stacey Knight  19 , Lise L Gluud  20   21 , Kirsten Vistisen  22 , Einar S Björnsson  23   24 , Magnus O Ulfarsson  5   25 , Patrick Sulem  5 , Hilma Holm  5 , Ole B Pedersen  14   21 , Sisse R Ostrowski  7   21 , Daniel F Gudbjartsson  5   26 , Thorunn Rafnar  5 , Kari Stefansson  5 , Ulrik Lassen  21   27 , Hans-Christian Pommergaard  21   28 , Jens G Hillingsø  21   28 , Jesper B Andersen  4 , Henning Bundgaard  1   21 , Stefan Stender  3   21
Affiliations

Genome-wide meta-analysis identifies nine loci associated with higher risk of hepatocellular carcinoma development

Jonas Ghouse et al. JHEP Rep. .

Abstract

Background & aims: The genetic underpinnings of hepatocellular carcinoma (HCC) remain largely unknown. Thus, we aimed to identify new genetic risk loci for HCC.

Methods: We performed a genome-wide association study (GWAS) meta-analysis of 11 cohorts with validation in two independent cohorts. The identified variants were tested for effects on other hepatobiliary endpoints, and on incident HCC stratified by underlying risk factors. Mendelian randomization was used to assess the causal effects of a range of traits on the risk of HCC.

Results: In meta-analyses totaling 6,540 cases and 2,096,759 controls, we identified 10 associations with HCC, of which five (in KLF15, HSD17B13, APOE, HFE, and MTARC1) have not previously been implicated in HCC at genome-wide statistical significance. Known associations in PNPLA3, TM6SF2, TERT, IFNL4, and HLA-DP1 were confirmed. All associations except KLF15 were validated in independent cohorts totaling 7,630 cases and 733,689 controls. The largest per-allele effect was seen for TM6SF2 (beta = 0.61) followed by PNPLA3 (0.55), HFE (0.45), IFNL4 (0.31), APOE (0.27), HSD17B13, HLA-DP1, and TERT (all 0.21), and MTARC1 (0.17). The identified variants had comparable effects on incident HCC in individuals with prevalent obesity, a high alcohol intake, diabetes, or cirrhosis. Mendelian randomization analyses confirmed the causal role of obesity in HCC. We found strong correlations between genetic effects on HCC and hepatic steatosis (r2 = 0.75), and HCC and cirrhosis (r2 = 0.69), whereas only three loci (APOE, HFE, and TERT) had concordant effects on HCC and biliary tract cancer.

Conclusions: We identified and validated nine genetic variants associated with an increased risk of HCC development.

Impact and implications: The genetic underpinnings of HCC remain largely unknown. In this genome-wide association meta-analysis totaling 6,540 cases with HCC and 2.1 million controls, we identified and validated nine genetic loci to associate with the risk of HCC. A deeper insight into genetic factors that affect the risk of HCC could improve our ability to predict and ultimately prevent or treat this deadly cancer.

Keywords: Biliary tract cancer; Cirrhosis; HCC; MASLD; PNPLA3.

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Conflict of interest statement

The authors who are affiliated with deCODE genetics/Amgen declare competing financial interests as employees. JG has received lecture fee from Illumina. SV has served as consultant for Albireo and received research funding from Moderna Therapeutics, with no relevance to this study. SB is a board member for Proscion A/S and Intomics A/S. JBA has received consulting fees from AstraZeneca (Nordic), QED Therapeutics, and Flagship Pioneering as well as project funding from Incyte Corp and ADCendo (not related to this study). HB receives lecture fees from Bristol-Myers Squibb, Merck Sharp and Dohme. SS has served as consultant for Regeneron and received a lecture fee from Amgen. All other authors have no conflict of interest to declare. Please refer to the accompanying ICMJE disclosure forms for further details.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Overview of the study design. CA, cross-ancestry; CHB-CC/DBDS, Copenhagen Hospital Biobank Cancer Cohort and Danish Blood Donor Study; EA, East Asian ancestry; EUR, European ancestry; HCC, hepatocellular carcinoma; UKB, UK Biobank; EstBB, Estonian Biobank; PLCO, The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.
Fig. 2
Fig. 2
Manhattan plots for HCC GWAS meta-analyses in individuals with European ancestry (A), East Asian ancestry (B), and cross-ancestry (C). The dashed horizontal lines depict the threshold for genome-wide significance, p <5x10-8. GWAS, genome-wide association study; HCC, hepatocellular carcinoma.
Fig. 3
Fig. 3
Comparison of genetic associations with HCC, hepatic steatosis, cirrhosis, and biliary tract cancer. Variants that had stronger effects (p <0.05 by Cochran’s Q test) on HCC compared with steatosis, cirrhosis, or biliary tract cancer, respectively, are in blue. In all analyses, HCC effects were derived from the cross-ancestry meta-analysis in the present study. (A) Effects of 15 previously reported hepatic steatosis variants and eight HCC variants identified in this study, totaling 18 distinct signals. The proton density fat fraction (PDFF) effects were derived from hepatic magnetic resonance imaging (MRI) in UKB. (B) Effects of 15 previously reported cirrhosis variants and 10 HCC variants from this study, totaling 16 distinct signals. The cirrhosis effects were derived from a previous GWAS. (C) Effects of eight HCC variants identified in the present study. Effects on biliary tract cancer were derived from European-ancestry UKB participants (893 cases and 458,134 controls). The dashed identity line (y  =  x) is shown for reference in each panel. GWAS, genome-wide association study; HCC, hepatocellular carcinoma; UKB, UK Biobank.
Fig. 4
Fig. 4
Mendelian randomization analyses of the effect of BMI and alcohol intake on HCC. The HCC odds ratios are for a genetically proxied 1-SD increase in BMI (top) or alcohol consumption (bottom), respectively. HCC, hepatocellular carcinoma.
See this image and copyright information in PMC

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