A genome-wide association study identified a variant in the PNPLA3 gene (rs738409; I148M) associated with increased hepatic fat content and inflammation in nonalcoholic fatty liver disease (NAFLD). This variant was most common in Hispanics, who are most susceptible to NAFLD. PNPLA3 encodes a protein of unknown function in the patatin-like phospholipase family. Another variant, PNPLA3-S453I, was associated with lower hepatic fat content in African-Americans, who have the lowest risk of NAFLD. These findings suggest that genetic variation in PNPLA3 contributes to ethnic and individual differences in hepatic fat content and susceptibility to NAFLD. PNPLA3 is involved in lipid metabolism, and its variants may influence hepatic fat accumulation. The I148M variant was strongly associated with increased hepatic fat content and liver inflammation, independent of BMI, diabetes, and ancestry. The S453I variant was associated with lower hepatic fat content in African-Americans. These variants may represent loss-of-function and gain-of-function alleles, respectively, affecting hepatic fat content through different mechanisms. The study also found that the PNPLA3-I148M variant was associated with elevated serum levels of alanine aminotransferase (ALT), indicating liver inflammation, particularly in Hispanics. The variant did not significantly affect glucose homeostasis or lipoprotein metabolism, suggesting that increased hepatic fat does not inevitably lead to insulin resistance. The study highlights the role of PNPLA3 in determining hepatic fat content and susceptibility to NAFLD. Genetic variation in PNPLA3 accounts for a large fraction of ethnic differences in the propensity to accumulate excess fat in the liver. Further research is needed to determine the specific mechanisms by which these variants affect lipid metabolism and liver function.A genome-wide association study identified a variant in the PNPLA3 gene (rs738409; I148M) associated with increased hepatic fat content and inflammation in nonalcoholic fatty liver disease (NAFLD). This variant was most common in Hispanics, who are most susceptible to NAFLD. PNPLA3 encodes a protein of unknown function in the patatin-like phospholipase family. Another variant, PNPLA3-S453I, was associated with lower hepatic fat content in African-Americans, who have the lowest risk of NAFLD. These findings suggest that genetic variation in PNPLA3 contributes to ethnic and individual differences in hepatic fat content and susceptibility to NAFLD. PNPLA3 is involved in lipid metabolism, and its variants may influence hepatic fat accumulation. The I148M variant was strongly associated with increased hepatic fat content and liver inflammation, independent of BMI, diabetes, and ancestry. The S453I variant was associated with lower hepatic fat content in African-Americans. These variants may represent loss-of-function and gain-of-function alleles, respectively, affecting hepatic fat content through different mechanisms. The study also found that the PNPLA3-I148M variant was associated with elevated serum levels of alanine aminotransferase (ALT), indicating liver inflammation, particularly in Hispanics. The variant did not significantly affect glucose homeostasis or lipoprotein metabolism, suggesting that increased hepatic fat does not inevitably lead to insulin resistance. The study highlights the role of PNPLA3 in determining hepatic fat content and susceptibility to NAFLD. Genetic variation in PNPLA3 accounts for a large fraction of ethnic differences in the propensity to accumulate excess fat in the liver. Further research is needed to determine the specific mechanisms by which these variants affect lipid metabolism and liver function.