Rare Atg7 Genetic Variants Predispose to Severe Fatty Liver Disease

Background&Aims: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease and has a strong heritable component. The aim of this study was to identify new genes involved in NAFLD pathogenesis. Methods: We examined rare variants captured by whole-exome sequencing in individuals with severe fibrosis or hepatocellular carcinoma due to NAFLD (severe NAFLD, n=301) after variant prioritization. We replicated the results in the UK Biobank and the Liver biopsy cohort (n=2268). Results: We observed an enrichment of the p.P426L variant (rs143545741 C>T; OR=7.2, 2.3-17.3; p<0.001) of autophagy-related 7 (ATG7), involved in lipo-autophagy and steatohepatitis development in mice, in severe NAFLD vs. the general population. In severe NAFLD, we further observed a higher burden of rare variants (OR=13.9, 1.9-611; p=0.002) in the conserved ATG7 C-terminal domain, and of the low-frequency p.V471A variant (rs36117895 T>C; MAF=0.060 vs. 0.035; OR=1.7, 1.2-2.5; p=0.003). In the UK Biobank cohort, the p.V471A variant was associated with NAFLD (p=0.009) and liver disorders (p=0.004). In the Liver biopsy cohort, the p.V471A variant was linked with severe fibrosis, particularly in those with severe steatosis (p=0.002). Moreover, p.V471A was an independent predictor of hepatocellular ballooning (p=0.007). Hepatic ATG7 expression correlated with suppression of the TNFα pathway, which was conversely upregulated in p.V471A carriers (n=125 with available transcriptomic). ATG7 protein localized to non-parenchymal cells and predominantly in periportal hepatocytes, more so in the presence of ballooning. Finally, we confirmed that in vitro the p.P426L and p.V471A variants result in a protein loss-of-function. Conclusion: We identified novel rare and low-frequency ATG7 variants contributing to severe NAFLD. The underlying mechanism may involve impairment of autophagy and facilitation of hepatocellular ballooning degeneration.