title: Genetic regulation of mouse liver metabolite levels.
abstract: We profiled and analyzed 283 metabolites representing eight major classes of molecules including Lipids, Carbohydrates, Amino Acids, Peptides, Xenobiotics, Vitamins and Cofactors, Energy Metabolism, and Nucleotides in mouse liver of 104 inbred and recombinant inbred strains. We find that metabolites exhibit a wide range of variation, as has been previously observed with metabolites in blood serum. Using genome-wide association analysis, we mapped 40% of the quantified metabolites to at least one locus in the genome and for 75% of the loci mapped we identified at least one candidate gene by local expression QTL analysis of the transcripts. Moreover, we validated 2 of 3 of the significant loci examined by adenoviral overexpression of the genes in mice. In our GWAS results, we find that at significant loci the peak markers explained on average between 20 and 40% of variation in the metabolites. Moreover, 39% of loci found to be regulating liver metabolites in mice were also found in human GWAS results for serum metabolites, providing support for similarity in genetic regulation of metabolites between mice and human. We also integrated the metabolomic data with transcriptomic and clinical phenotypic data to evaluate the extent of co-variation across various biological scales.
authors.affiliation: Division of Cardiology, Department of Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: Anatole
authors.initials: A
authors.lastname: Ghazalpour
authors.affiliation: Division of Cardiology, Department of Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bennett
authors.affiliation: Division of Cardiology, Department of Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Shih
authors.affiliation: Division of Cardiology, Department of Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: Nam
authors.initials: N
authors.lastname: Che
authors.affiliation: Department of Molecular Cell and Developmental Biology, UCLA, Los Angeles, CA, USA.
authors.forename: Luz
authors.initials: L
authors.lastname: Orozco
authors.affiliation: Department of Human Genetics, UCLA, Los Angeles, CA, USA.
authors.forename: Calvin
authors.initials: C
authors.lastname: Pan
authors.affiliation: Division of Cardiology, Department of Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: Raffi
authors.initials: R
authors.lastname: Hagopian
authors.affiliation: Department of Applied Genomics, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Aiqing
authors.initials: A
authors.lastname: He
authors.affiliation: Department of Applied Genomics, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Kayne
authors.affiliation: Department of Applied Genomics, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Wen-pin
authors.initials: WP
authors.lastname: Yang
authors.affiliation: Department of Atherosclerosis Drug Discovery, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Kirchgessner
authors.affiliation: Division of Cardiology, Department of Medicine, UCLA, Los Angeles, CA, USA Department of Human Genetics, UCLA, Los Angeles, CA, USA jlusis@mednet.ucla.edu.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D008099:Liver / Q000378:metabolism*; D055432:Metabolomics; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*
chemical_list: D001798:Blood Proteins
keywords: QTL; genome‐wide association; local eQTL; metabolome; transcriptome