title: The sequenced rat brain transcriptome--its use in identifying networks predisposing alcohol consumption.
abstract: A quantitative genetic approach, which involves correlation of transcriptional networks with the phenotype in a recombinant inbred (RI) population and in selectively bred lines of rats, and determination of coinciding quantitative trait loci for gene expression and the trait of interest, has been applied in the present study. In this analysis, a novel approach was used that combined DNA-Seq data, data from brain exon array analysis of HXB/BXH RI rat strains and six pairs of rat lines selectively bred for high and low alcohol preference, and RNA-Seq data (including rat brain transcriptome reconstruction) to quantify transcript expression levels, generate co-expression modules and identify biological functions that contribute to the predisposition of consuming varying amounts of alcohol. A gene co-expression module was identified in the RI rat strains that contained both annotated and unannotated transcripts expressed in the brain, and was associated with alcohol consumption in the RI panel. This module was found to be enriched with differentially expressed genes from the selected lines of rats. The candidate genes within the module and differentially expressed genes between high and low drinking selected lines were associated with glia (microglia and astrocytes) and could be categorized as being related to immune function, energy metabolism and calcium homeostasis, as well as glial-neuronal communication. The results of the present study show that there are multiple combinations of genetic factors that can produce the same phenotypic outcome. Although no single gene accounts for predisposition to a particular level of alcohol consumption in every animal model, coordinated differential expression of subsets of genes in the identified pathways produce similar phenotypic outcomes.
  
  
  METHODS
  The datasets supporting the results of the present study are available at http://phenogen.ucdenver.edu.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Saba
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Flink
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Vanderlinden
authors.affiliation: Laboratory of Pharmacogenetics of Alcoholism, Molecular & Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Yedy
authors.initials: Y
authors.lastname: Israel
authors.affiliation: Laboratory of Pharmacogenetics of Alcoholism, Molecular & Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Lutske
authors.initials: L
authors.lastname: Tampier
authors.affiliation: Neuroscience Institute, National Research Council of Italy, Section of Cagliari, Monserrato, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Colombo
authors.affiliation: Department of Alcohol, Drugs and Addiction, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Kalervo
authors.initials: K
authors.lastname: Kiianmaa
authors.affiliation: Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Bell
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
authors.forename: Morton P
authors.initials: MP
authors.lastname: Printz
authors.affiliation: Department of Pediatrics, University of California, Irvine, Irvine, CA, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Flodman
authors.affiliation: Committee on the Neurobiology of Addiction Disorders, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: George
authors.initials: G
authors.lastname: Koob
authors.affiliation: Committee on the Neurobiology of Addiction Disorders, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Heather N
authors.initials: HN
authors.lastname: Richardson
authors.affiliation: National Supercomputing Center for Energy and Environment, University of Nevada, Las Vegas, Nevada, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lombardo
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA.|Department of Pharmacology, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Paula L
authors.initials: PL
authors.lastname: Hoffman
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA.|Department of Pharmacology, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Boris
authors.initials: B
authors.lastname: Tabakoff
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D030561:Databases, Nucleic Acid; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D008297:Male; D051381:Rats; D011914:Rats, Inbred BN; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D011995:Recombination, Genetic; D059467:Transcriptome
keywords: HXB RI rat strains; alcohol consumption; gene expression; neuroinflammation; rat selected lines