Understanding the genetic architecture of fatty liver disease

Abstract: Non-alcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease, ranging from simple steatosis to more severe conditions, namely non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). NAFLD has a strong genetic component, and its heritability depends on environmental factors and ethnicity. So far, genome-wide association studies were able to explain only a small fraction of its heritability, indicating the presence of missing heritability. Moreover, despite more than 20% of the general population and more than 70% of individuals with obesity have fatty liver, only a minority of individuals will progress to end stage liver disease. In the first study, we used polygenic risk scores (PRS) based on 5 known common genetic determinants of NAFLD to stratify the risk of HCC in individuals with dysmetabolism. We showed the ability of our PRS to predict the full spectrum of NAFLD and HCC both in high-risk individuals and in the general population. Additionally, we demonstrated a causal association between genetic predisposition to hepatic steatosis and HCC using a Mendelian Randomization approach. In the second study, we performed an exome-wide association study of alanine aminotransferase (ALT), a biomarker of liver fat and damage, to identify other genetic determinants of fatty liver disease. We found two missense variants on GPAM and APOE genes, robustly associated with liver fat content and chronic liver disease. Finally, in the third study, we performed a gene-environment-wide interaction study (GEWIS) of ALT to evaluate the role of gene-environment interactions in fatty liver disease susceptibility and to identify new genetic determinant of NAFLD. We found a new locus interacting with body mass index (BMI), the strongest environmental risk factor for NAFLD, associated with liver fat and chronic liver disease, but not with ALT. In conclusion, these findings strongly support a causal relationship between liver fat accumulation and severe liver disease. Moreover, new genetic determinants of fatty liver identified by our analyses may be used for risk stratification of advanced liver disease and HCC, and exploited as potential drug targets.