Hui, Simon TParks, Brian WOrg, ElinNorheim, FrodeChe, NamPan, CalvinCastellani, Lawrence WCharugundla, SaradaDirks, Darwin LPsychogios, NikolaosNeuhaus, IsaacGerszten, RobertKirchgessner, ToddGargalovic, Peter SLusis, Aldons J2015-08-032015Hui, S. T., B. W. Parks, E. Org, F. Norheim, N. Che, C. Pan, L. W. Castellani, et al. 2015. “The genetic architecture of NAFLD among inbred strains of mice.” eLife 4 (1): e05607. doi:10.7554/eLife.05607. http://dx.doi.org/10.7554/eLife.05607.2050-084Xhttp://nrs.harvard.edu/urn-3:HUL.InstRepos:17820829To identify genetic and environmental factors contributing to the pathogenesis of non-alcoholic fatty liver disease, we examined liver steatosis and related clinical and molecular traits in more than 100 unique inbred mouse strains, which were fed a diet rich in fat and carbohydrates. A >30-fold variation in hepatic TG accumulation was observed among the strains. Genome-wide association studies revealed three loci associated with hepatic TG accumulation. Utilizing transcriptomic data from the liver and adipose tissue, we identified several high-confidence candidate genes for hepatic steatosis, including Gde1, a glycerophosphodiester phosphodiesterase not previously implicated in triglyceride metabolism. We confirmed the role of Gde1 by in vivo hepatic over-expression and shRNA knockdown studies. We hypothesize that Gde1 expression increases TG production by contributing to the production of glycerol-3-phosphate. Our multi-level data, including transcript levels, metabolite levels, and gut microbiota composition, provide a framework for understanding genetic and environmental interactions underlying hepatic steatosis. DOI: http://dx.doi.org/10.7554/eLife.05607.001en-UShepatic steatosisgenome-wide associationtranscriptomemicrobiomemetabolomemouseJournal Article2015-08-0310.7554/eLife.05607