Identification of candidate genes for alcohol preference by expression profiling of congenic rat strains

Lucinda G. Carr, Mark W. Kimpel, Tiebing Liang, Jeanette McClintick, Kevin McCall, Melissa Morse, Howard Edenberg

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Background: A highly significant quantitative trait locus (QTL) on chromosome 4 that influenced alcohol preference was identified by analyzing crosses between the iP and iNP rats. Congenic strains in which the iP chromosome 4 QTL interval was transferred to the iNP (NP.P) exhibited the expected increase in alcohol consumption compared with the iNP background strain. This study was undertaken to identify genes in the chromosome 4 QTL interval that might contribute to the differences in alcohol consumption between the alcohol-naïve congenic and background strains. Methods: RNA from 5 brain regions from each of 6 NP.P and 6 iNP rats was labeled and analyzed separately on an Affymetrix Rat Genome 230 2.0 microarray to look for both cis-regulated and trans-regulated genes. Expression levels were normalized using robust multi-chip average (RMA). Differential gene expression was validated using quantitative real-time polymerase chain reaction. Five individual brain regions (nucleus accumbens, frontal cortex, amygdala, hippocampus, and striatum) were analyzed to detect differential expression of genes within the introgressed QTL interval, as well as genes outside that region. To increase the power to detect differentially expressed genes, combined analyses (averaging data from the 5 discrete brain regions of each animal) were also carried out. Results: Analyses within individual brain regions that focused on genes within the QTL interval detected differential expression in all 5 brain regions; a total of 35 genes were detected in at least 1 region, ranging from 6 genes in the nucleus accumbens to 22 in the frontal cortex. Analysis of the whole genome detected very few differentially expressed genes outside the QTL. Combined analysis across brain regions was more powerful. Analysis focused on the genes within the QTL interval confirmed 19 of the genes detected in individual regions and detected 15 additional genes. Whole genome analysis detected 1 differentially expressed gene outside the interval. Conclusions: Cis-regulated candidate genes for alcohol consumption were identified using microarray profiling of gene expression differences in congenic animals carrying a QTL for alcohol preference.

Original languageEnglish
Pages (from-to)1089-1098
Number of pages10
JournalAlcoholism: Clinical and Experimental Research
Volume31
Issue number7
DOIs
StatePublished - Jul 2007

Fingerprint

Genetic Association Studies
Quantitative Trait Loci
Rats
Genes
Alcohols
Chromosomes, Human, Pair 4
Brain
Alcohol Drinking
Nucleus Accumbens
Frontal Lobe
Genome
Chromosomes
Congenic Animals
Gene Expression
Microarrays
Gene expression
Gene Expression Profiling
Amygdala
Animals
Real-Time Polymerase Chain Reaction

Keywords

  • Alcohol Consumption
  • Candidate Genes
  • Congenic Rats
  • Microarray
  • QTL

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology

Cite this

Identification of candidate genes for alcohol preference by expression profiling of congenic rat strains. / Carr, Lucinda G.; Kimpel, Mark W.; Liang, Tiebing; McClintick, Jeanette; McCall, Kevin; Morse, Melissa; Edenberg, Howard.

In: Alcoholism: Clinical and Experimental Research, Vol. 31, No. 7, 07.2007, p. 1089-1098.

Research output: Contribution to journalArticle

Carr, Lucinda G. ; Kimpel, Mark W. ; Liang, Tiebing ; McClintick, Jeanette ; McCall, Kevin ; Morse, Melissa ; Edenberg, Howard. / Identification of candidate genes for alcohol preference by expression profiling of congenic rat strains. In: Alcoholism: Clinical and Experimental Research. 2007 ; Vol. 31, No. 7. pp. 1089-1098.
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T1 - Identification of candidate genes for alcohol preference by expression profiling of congenic rat strains

AU - Carr, Lucinda G.

AU - Kimpel, Mark W.

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AU - McCall, Kevin

AU - Morse, Melissa

AU - Edenberg, Howard

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N2 - Background: A highly significant quantitative trait locus (QTL) on chromosome 4 that influenced alcohol preference was identified by analyzing crosses between the iP and iNP rats. Congenic strains in which the iP chromosome 4 QTL interval was transferred to the iNP (NP.P) exhibited the expected increase in alcohol consumption compared with the iNP background strain. This study was undertaken to identify genes in the chromosome 4 QTL interval that might contribute to the differences in alcohol consumption between the alcohol-naïve congenic and background strains. Methods: RNA from 5 brain regions from each of 6 NP.P and 6 iNP rats was labeled and analyzed separately on an Affymetrix Rat Genome 230 2.0 microarray to look for both cis-regulated and trans-regulated genes. Expression levels were normalized using robust multi-chip average (RMA). Differential gene expression was validated using quantitative real-time polymerase chain reaction. Five individual brain regions (nucleus accumbens, frontal cortex, amygdala, hippocampus, and striatum) were analyzed to detect differential expression of genes within the introgressed QTL interval, as well as genes outside that region. To increase the power to detect differentially expressed genes, combined analyses (averaging data from the 5 discrete brain regions of each animal) were also carried out. Results: Analyses within individual brain regions that focused on genes within the QTL interval detected differential expression in all 5 brain regions; a total of 35 genes were detected in at least 1 region, ranging from 6 genes in the nucleus accumbens to 22 in the frontal cortex. Analysis of the whole genome detected very few differentially expressed genes outside the QTL. Combined analysis across brain regions was more powerful. Analysis focused on the genes within the QTL interval confirmed 19 of the genes detected in individual regions and detected 15 additional genes. Whole genome analysis detected 1 differentially expressed gene outside the interval. Conclusions: Cis-regulated candidate genes for alcohol consumption were identified using microarray profiling of gene expression differences in congenic animals carrying a QTL for alcohol preference.

AB - Background: A highly significant quantitative trait locus (QTL) on chromosome 4 that influenced alcohol preference was identified by analyzing crosses between the iP and iNP rats. Congenic strains in which the iP chromosome 4 QTL interval was transferred to the iNP (NP.P) exhibited the expected increase in alcohol consumption compared with the iNP background strain. This study was undertaken to identify genes in the chromosome 4 QTL interval that might contribute to the differences in alcohol consumption between the alcohol-naïve congenic and background strains. Methods: RNA from 5 brain regions from each of 6 NP.P and 6 iNP rats was labeled and analyzed separately on an Affymetrix Rat Genome 230 2.0 microarray to look for both cis-regulated and trans-regulated genes. Expression levels were normalized using robust multi-chip average (RMA). Differential gene expression was validated using quantitative real-time polymerase chain reaction. Five individual brain regions (nucleus accumbens, frontal cortex, amygdala, hippocampus, and striatum) were analyzed to detect differential expression of genes within the introgressed QTL interval, as well as genes outside that region. To increase the power to detect differentially expressed genes, combined analyses (averaging data from the 5 discrete brain regions of each animal) were also carried out. Results: Analyses within individual brain regions that focused on genes within the QTL interval detected differential expression in all 5 brain regions; a total of 35 genes were detected in at least 1 region, ranging from 6 genes in the nucleus accumbens to 22 in the frontal cortex. Analysis of the whole genome detected very few differentially expressed genes outside the QTL. Combined analysis across brain regions was more powerful. Analysis focused on the genes within the QTL interval confirmed 19 of the genes detected in individual regions and detected 15 additional genes. Whole genome analysis detected 1 differentially expressed gene outside the interval. Conclusions: Cis-regulated candidate genes for alcohol consumption were identified using microarray profiling of gene expression differences in congenic animals carrying a QTL for alcohol preference.

KW - Alcohol Consumption

KW - Candidate Genes

KW - Congenic Rats

KW - Microarray

KW - QTL

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