Beschreibung:
<jats:p>Using publicly available data from inbred mouse strains, we conducted a genome‐wide association study to identify loci that accounted for liver‐related phenotypes between C57BL/6J and A/J mice fed a Paigen diet. We confirmed genome‐wide significant associations for hepatic cholesterol (chromosome 10A2) and serum total bile acid concentration (chromosome 12E) and identified a new locus for liver inflammation (chromosome 7C). Analysis of consomic mice confirmed that chromosome 12 A/J alleles accounted for the variance in serum total bile acid concentrations and had pleiotropic effects on liver mass, serum cholesterol, and serum alanine aminotransferase activity. Using an affected‐only haplotype analysis among strains, we refined the chromosome 12E signal to a 1.95 Mb linkage disequilibrium block containing only one gene, sel‐1 suppressor of lin‐12‐like (<jats:italic toggle="yes">Sel1l</jats:italic>). RNA sequencing and immunoblotting demonstrated that the risk allele locally conferred reduced expression of SEL1L in liver and distantly down‐regulated pathways associated with hepatocyte nuclear factor 1 homeobox A (<jats:italic toggle="yes">Hnf1a</jats:italic>) and hepatocyte nuclear factor 4A (<jats:italic toggle="yes">Hnf4a</jats:italic>), known modifiers of bile acid transporters and metabolic traits. Consistent with these data, knockdown of <jats:italic toggle="yes">SEL1L</jats:italic> in HepG2 cells resulted in reduced HNF1A and HNF4A and increased bile acids in culture media; it further captured multiple molecular signatures observed in consomic mouse livers with reduced SEL1L. Finally, dogs harboring a <jats:italic toggle="yes">SEL1L</jats:italic> mutation and <jats:italic toggle="yes">Sel1l</jats:italic>
<jats:sup>+/−</jats:sup> mice fed a Paigen diet had significantly increased serum total bile acid concentrations, providing independent confirmation linking SEL1L to bile acid metabolism. <jats:italic toggle="yes">Conclusion</jats:italic>: Genetic analyses of inbred mouse strains identified loci affecting different liver‐related traits and implicated <jats:italic toggle="yes">Sel1l</jats:italic> as a significant determinant of serum bile acid concentration. (H<jats:sc>epatology</jats:sc> 2016;63:1943‐1956)</jats:p>