Integrative Polygenic Genetic Studies of Non-alcoholic Fatty Liver Disease Summary Nonalcoholic fatty liver disease (NAFLD) is caused by hepatic steatosis (lipid accumulation), affects up to 29 million adults in the U.S. and has become the leading cause of liver disease. NAFLD can lead to liver cirrhosis and hepatocellular carcinoma. There are few effective ways to prevent or treat NAFLD. A better understanding of NAFLD etiology is needed to improve its diagnosis and treatment. NAFLD is heritable (genetically influenced) and identified common variants that explain ~20% of heritability of this trait, suggesting that more causal variants that affect this trait remain to be discovered. While histology has historically been used to define NAFLD steatosis, NAFLD is now routinely diagnosed using non invasive imaging or elevated ALT/AST without the presence of other liver diseases. We recently published the world’s largest cross ancestry GWAS analysis of serum ALT/AST/ALP GWAS where we identified >300 genome wide significant variants that associate with these traits; 23 of them also associated with increased hepatic steatosis assessed in 7600 individuals using liver imaging. We showed that a polygenic risk score (PRS) from the ALT but not AST or ALP genome wide significant variants was able to predict steatosis, cirrhosis, and HCC. Here, we have assembled the largest collection of multiethnic samples with hepatic steatosis measured with liver imaging or NAFLD diagnosed by international classification of disease code with genome wide data also available. We hypothesize that (1) common and low frequency variants contribute to NAFLD variation and risk (2) identified variants in aggregate will improve risk prediction for liver steatosis, cirrhosis and HCC compared to single variants and (3) GWAS NAFLD prioritized genes, when targeted, will function autonomously in hepatocytes to cause steatosis. The objective of this application is to carry out a GWAS meta analysis of NAFLD across imaging or ICD diagnosed NAFLD. A PRS will be created from verified NAFLD associated variants effect and assessed for its ability to predict, steatosis, cirrhosis, HCC. We will annotate verified NAFLD associated variants to identify target genes for follow up functional studies for effects on steatosis alone and in combination. Results from this work will help define the genetic and metabolic mechanisms that cause NAFLD and inform development of new biomarkers as well as potential therapeutics for this condition.