Genome-wide Association Study in Mice Identifies Loci Affecting Liver-related Phenotypes Including Sel1l Influencing Serum Bile Acids (original) (raw)

2016, Hepatology (Baltimore, Md.)

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 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 also 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, Sel1l. RNA-seq and immunoblotting demonstrated that the risk allele locally conferred reduced expression of SEL1L in liver and distantly downregulates pathways associa...