Dissecting the effect of genetic variation on the hepatic expression of drug disposition genes across the collaborative cross mouse strains

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• dc.contributor.author Nachshon, Aharon
• dc.contributor.author Abu-Toamih Atamni, Hanifa Jalal
• dc.contributor.author Steuerman, Yael
• dc.contributor.author Sheikh-Hamed, Roa'a
• dc.contributor.author Dorman, Alexandra
• dc.contributor.author Mott, Richard
• dc.contributor.author Dohm, Juliana C.
• dc.contributor.author Lehrach, Hans
• dc.contributor.author Sultan, Marc
• dc.contributor.author Shamir, Ron
• dc.contributor.author Sauer, Sascha
• dc.contributor.author Himmelbauer, Heinz
• dc.contributor.author Iraqi, Fuad A.
• dc.contributor.author Gat-Viks, Irit
• dc.date.accessioned 2024-03-26T07:13:54Z
• dc.date.available 2024-03-26T07:13:54Z
• dc.date.issued 2016
• dc.description.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.
• dc.description.sponsorship This work was supported by the European Commission [FP7/2007-2013, under grant agreement no. 262055 (ESGI)], by the Israeli Centers of Research Excellence (I-CORE): Center No. 41/11, by the Broad-ISF grant 1168/14, and by the Wellcome Trust grants 090532/Z/09/Z, 085906/Z/08/Z, 083573/Z/07/Z, and 075491/Z/04. Research in the IG lab was supported by the European Research Council (637885), and by the Israeli Science Foundation (ISF) grant 1643/13. YS was partially supported by the Edmond J. Safra Center for Bioinformatics at Tel Aviv University IG is a Faculty Fellow of the Edmond J. Safra Center for Bioinformatics at Tel Aviv University and an Alon Fellow. RS was supported in part by the Raymond and Beverly Sackler Chair in Bioinformatics.
• dc.format.mimetype application/pdf
• dc.identifier.citation Nachshon A, Abu-Toamih HJ, Steuerman Y, Sheikh-Hamed R, Dorman A, Mott R, et al. Dissecting the effect of genetic variation on the hepatic expression of drug disposition genes across the collaborative cross mouse strains. Front Genet. 2016 Oct 5;7:172. DOI: 10.3389/fgene.2016.00172
• dc.identifier.doi http://dx.doi.org/10.3389/fgene.2016.00172
• dc.identifier.issn 1664-8021
• dc.identifier.uri http://hdl.handle.net/10230/59566
• dc.language.iso eng
• dc.publisher Frontiers
• dc.relation.ispartof Frontiers in Genetics. 2016 Oct 5;7:172
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/262055
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/637885
• dc.rights © 2016 Nachshon, Abu-Toamih Atamni, Steuerman, Sheikh-Hamed, Dorman, Mott, Dohm, Lehrach, Sultan, Shamir, Sauer, Himmelbauer, Iraqi and Gat-Viks. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Collaborative cross mouse strains
• dc.subject.keyword Hepatic drug disposition
• dc.subject.keyword eQTLs analysis
• dc.subject.keyword Transcript isoforms
• dc.subject.keyword Genetic variation
• dc.title Dissecting the effect of genetic variation on the hepatic expression of drug disposition genes across the collaborative cross mouse strains
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion