Genome-wide association study identifies high-impact susceptibility loci for hepatocellular carcinoma in North America

Background & Aims: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have increased risk for hepatocellular carcinoma (HCC). However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European-descent populations (EDP). Approach & Results: We conducted a two-stage genome-wide association study (GWAS) on HCC not affected by hepatitis B virus infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted meta-analysis. All analyses were conducted in the presence and absence of hepatitis C virus (HCV). The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for non-viral HCC: 3p22.1, MOBP , rs9842969, [0.51, (0.40-0.65)]; 5p15.33, TERT , rs2242652, [0.70, (0.62-0.79)]; 19q13.11, TM6SF2 , rs58542926, [1.49, (1.29-1.72)]; 19p13.11 MAU2 , rs58489806, [1.53, (1.33-1.75)]; and 22q13.31, PNPLA3, rs738409, [1.66, (1.51-1.83)]. One region was identified for HCV-induced HCC: 6p21.31, HLA-DQB1 , rs9275224, [0.79, (0.74-0.84)]. A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for non-viral–related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. Conclusions: Our GWAS highlights novel genetic susceptibility of non-viral HCC among EDP from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.