Nachshon, A;
Atamni, HJA-T;
Steuerman, Y;
Sheikh-Hamed, R;
Dorman, A;
Mott, R;
Dohm, JC;
... Gat-Viks, I; + view all
(2016)
Dissecting the Effect of Genetic Variation on the Hepatic Expression of Drug Disposition Genes across the Collaborative Cross Mouse Strains.
Frontiers in Genetics
, 7
, Article 172. 10.3389/fgene.2016.00172.
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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.
| Type: | Article |
|---|---|
| Title: | Dissecting the Effect of Genetic Variation on the Hepatic Expression of Drug Disposition Genes across the Collaborative Cross Mouse Strains |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3389/fgene.2016.00172 |
| Publisher version: | http://dx.doi.org/10.3389/fgene.2016.00172 |
| Language: | English |
| Additional information: | © 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. |
| Keywords: | Collaborative cross mouse strains, hepatic drug disposition, eQTLs analysis, transcript isoforms, genetic variation, QUANTITATIVE TRAIT LOCI, SYSTEMS GENETICS, RNA-SEQ, MICE, DIVERSITY, POPULATIONS, PHARMACOGENETICS, SUSCEPTIBILITY, IDENTIFICATION, TRANSCRIPTOME |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1560490 |
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