title: Genome-wide association study in mice identifies loci affecting liver-related phenotypes including Sel1l influencing serum bile acids.
abstract: 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 (Sel1l). 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 (Hnf1a) and hepatocyte nuclear factor 4A (Hnf4a), known modifiers of bile acid transporters and metabolic traits. Consistent with these data, knockdown of SEL1L 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 SEL1L mutation and Sel1l(+/-) mice fed a Paigen diet had significantly increased serum total bile acid concentrations, providing independent confirmation linking SEL1L to bile acid metabolism.
  
  
  
  Genetic analyses of inbred mouse strains identified loci affecting different liver-related traits and implicated Sel1l as a significant determinant of serum bile acid concentration. (Hepatology 2016;63:1943-1956).
authors: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.|Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY.
authors: Wei
authors: W
authors: Wu
authors: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.
authors: Ami
authors: A
authors: Patel
authors: Department of Medical Genetics, University of Helsinki, Helsinki, Finland.|Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.|Department of Molecular Genetics, Folkhälsan Institute of Genetics, Helsinki, Finland.
authors: Kaisa
authors: K
authors: Kyöstilä
authors: Department of Medical Genetics, University of Helsinki, Helsinki, Finland.|Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.|Department of Molecular Genetics, Folkhälsan Institute of Genetics, Helsinki, Finland.
authors: Hannes
authors: H
authors: Lohi
authors: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.
authors: Nikol
authors: N
authors: Mladkova
authors: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.
authors: Krzysztof
authors: K
authors: Kiryluk
authors: JP Sulzberger Columbia Genome Center, College of Physicians and Surgeons, Columbia University, New York, NY.
authors: Xiaoyun
authors: X
authors: Sun
authors: Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY.
authors: Jay H
authors: JH
authors: Lefkowitch
authors: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.|Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY.
authors: Howard J
authors: HJ
authors: Worman
authors: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.
authors: Ali G
authors: AG
authors: Gharavi
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood*; D004285:Dogs; D005234:Fatty Liver / Q000235:genetics; D058685:Genetic Pleiotropy; D055106:Genome-Wide Association Study; D006239:Haplotypes; D056945:Hep G2 Cells; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011506:Proteins / Q000235:genetics*
chemical_list: D001647:Bile Acids and Salts; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; C496488:Hnf1a protein, mouse; C496593:Hnf4a protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C492169:Sel1h protein, mouse