title: Dissecting the Effect of Genetic Variation on the Hepatic Expression of Drug Disposition Genes across the Collaborative Cross Mouse Strains.
abstract: A central challenge in pharmaceutical research is to investigate genetic variation in response to drugs. The Collaborative Cross (CC) mouse reference population is a promising model for pharmacogenomic studies because of its large amount of genetic variation, genetic reproducibility, and dense recombination sites. While the CC lines are phenotypically diverse, their genetic diversity in drug disposition processes, such as detoxification reactions, is still largely uncharacterized. Here we systematically measured RNA-sequencing expression profiles from livers of 29 CC lines under baseline conditions. We then leveraged a reference collection of metabolic biotransformation pathways to map potential relations between drugs and their underlying expression quantitative trait loci (eQTLs). By applying this approach on proximal eQTLs, including eQTLs acting on the overall expression of genes and on the expression of particular transcript isoforms, we were able to construct the organization of hepatic eQTL-drug connectivity across the CC population. The analysis revealed a substantial impact of genetic variation acting on drug biotransformation, allowed mapping of potential joint genetic effects in the context of individual drugs, and demonstrated crosstalk between drug metabolism and lipid metabolism. Our findings provide a resource for investigating drug disposition in the CC strains, and offer a new paradigm for integrating biotransformation reactions to corresponding variations in DNA sequences.
authors.affiliation: Department of Cell Research and Immunology, Faculty of Life Sciences, Tel-Aviv University Tel-Aviv, Israel.
authors.forename: Aharon
authors.initials: A
authors.lastname: Nachshon
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel- Aviv University Tel-Aviv, Israel.
authors.forename: Hanifa J
authors.initials: HJ
authors.lastname: Abu-Toamih Atamni
authors.affiliation: Department of Cell Research and Immunology, Faculty of Life Sciences, Tel-Aviv University Tel-Aviv, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Steuerman
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel- Aviv University Tel-Aviv, Israel.
authors.forename: Roa'a
authors.initials: R
authors.lastname: Sheikh-Hamed
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel- Aviv University Tel-Aviv, Israel.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dorman
authors.affiliation: Genetics Institute, University College of London London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Mott
authors.affiliation: Genomics Unit, Center for Genomic RegulationBarcelona, Spain; Universitat Pompeu FabraBarcelona, Spain; Department of Biotechnology, University of Natural Resources and Life Sciences Vienna (BOKU)Vienna, Austria.
authors.forename: Juliane C
authors.initials: JC
authors.lastname: Dohm
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics Berlin, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Lehrach
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics Berlin, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Sultan
authors.affiliation: The Blavatnik School of Computer Science, Tel Aviv University Tel Aviv, Israel.
authors.forename: Ron
authors.initials: R
authors.lastname: Shamir
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular GeneticsBerlin, Germany; CU Systems Medicine, University of WürzburgWürzburg, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Sauer
authors.affiliation: Genomics Unit, Center for Genomic RegulationBarcelona, Spain; Universitat Pompeu FabraBarcelona, Spain; Department of Biotechnology, University of Natural Resources and Life Sciences Vienna (BOKU)Vienna, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Himmelbauer
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel- Aviv University Tel-Aviv, Israel.
authors.forename: Fuad A
authors.initials: FA
authors.lastname: Iraqi
authors.affiliation: Department of Cell Research and Immunology, Faculty of Life Sciences, Tel-Aviv University Tel-Aviv, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Gat-Viks
keywords: collaborative cross mouse strains; eQTLs analysis; genetic variation; hepatic drug disposition; transcript isoforms