Transcriptomics,Genomics

Dataset Information

43

A systems approach implicates a brain mitochondrial oxidative homeostasis co-expression network in genetic vulnerability to alcohol withdrawal


ABSTRACT: Differential gene expression between mouse distal chromsome 1 congenic and background and reciprocal congenic and background Genetic factors significantly affect vulnerability to alcohol dependence (alcoholism). We previously identified a quantitative trait locus on chromosome 1 (Adw1) with a large effect on predisposition to alcohol physiological dependence and associated withdrawal following both chronic and acute alcohol exposure in mice. We fine-mapped these loci to a 1.1-1.7 Mb interval syntenic with human 1q23.2-23.3. Adw1 interval genes show remarkable genetic variation among mice derived from the C57BL/6J and DBA/2J strains, the two most widely studied genetic animal models for alcohol-related traits. Here, we report the creation of a novel recombinant Adw1 congenic model (R2) in which the Adw1 interval from a donor C57BL/6J strain is introgressed onto a uniform, inbred DBA/2J genetic background. As expected, R2 mice demonstrate significantly less severe alcohol withdrawal compared to wild-type littermates. Additionally, comparing R2 and background strain animals, as well as reciprocal congenic (R8) and appropriate background strain animals, we assessed Adw1 dependent brain gene expression using microarray and quantitative PCR analyses. To our knowledge this includes the first Weighted Gene Co-expression Network Analysis using reciprocal congenic models. Importantly, this allows detection of co-expression patterns limited to one or common to both genetic backgrounds with high and low predisposition to alcohol withdrawal severity. The gene expression patterns (modules) in common contain genes related to oxidative phosphorylation, building upon human and animal model studies that implicate involvement of oxidative phosphorylation in alcohol use disorders. Finally, we demonstrate that administration of N-acetylcysteine, an FDA-approved antioxidant, significantly reduces symptoms of alcohol withdrawal (convulsions) in mice, thus validating a phenotypic role for this network. Taken together, these studies support the importance of mitochondrial oxidative homeostasis in alcohol withdrawal and identify this network as a valuable therapeutic target in human alcohol use disorders. Overall design: Whole brain, naïve, males. n=10 inbred C57BL/6J (B6), n=10 R8 small interval Chr 1 congenic (1.1 Mb D2 interval on B6 background), n=6 inbred DBA/2J (D2), n=6 R2 small interval Chr 1 congenic (10.2 Mb B6 interval on D2 background)

INSTRUMENT(S): Illumina MouseRef-8 v2.0 expression beadchip

SUBMITTER: Nikki Walter  

PROVIDER: GSE89281 | GEO | 2017-03-08

SECONDARY ACCESSION(S): PRJNA351237

REPOSITORIES: GEO

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Publications

A Systems Approach Implicates a Brain Mitochondrial Oxidative Homeostasis Co-expression Network in Genetic Vulnerability to Alcohol Withdrawal.

Walter Nicole A R NA   Denmark DeAunne L DL   Kozell Laura B LB   Buck Kari J KJ  

Frontiers in genetics 20160101


Genetic factors significantly affect vulnerability to alcohol dependence (alcoholism). We previously identified quantitative trait loci on distal mouse chromosome 1 with large effects on predisposition to alcohol physiological dependence and associated withdrawal following both chronic and acute alcohol exposure in mice (Alcdp1 and Alcw1, respectively). We fine-mapped these loci to a 1.1-1.7 Mb interval syntenic with human 1q23.2-23.3. Alcw1/Alcdp1 interval genes show remarkable genetic variatio  ...[more]

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