Selection for drinking in the dark alters brain gene coexpression networks

Ovidiu Iancu, Denesa Oberbeck, Priscila Darakjian, Pamela Metten, Shannon McWeeney, John Jr Crabbe, Robert Hitzemann

Research output: Contribution to journalArticle

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Abstract

Background: Heterogeneous stock (HS/NPT) mice have been used to create lines selectively bred in replicate for elevated drinking in the dark (DID). Both selected lines routinely reach a blood ethanol (EtOH) concentration (BEC) of 1.00 mg/ml or greater at the end of the 4-hour period of access in Day 2. The mechanisms through which genetic differences influence DID are currently unclear. Therefore, the current study examines the transcriptome, the first stage at which genetic variability affects neurobiology. Rather than focusing solely on differential expression (DE), we also examine changes in the ways that gene transcripts collectively interact with each other, as revealed by changes in coexpression patterns. Methods: Naïve mice (N = 48/group) were genotyped using the Mouse Universal Genotyping Array, which provided 3,683 informative markers. Quantitative trait locus (QTL) analysis used a marker-by-marker strategy with the threshold for a significant logarithm of odds (LOD) set at 10.6. Gene expression in the ventral striatum was measured using the Illumina Mouse 8.2 array. Differential gene expression and the weighted gene coexpression network analysis (WGCNA) were implemented largely as described elsewhere. Results: Significant QTLs for elevated BECs after DID were detected on chromosomes 4, 14, and 16; the latter 2 were associated with gene-poor regions. None of the QTLs overlapped with known QTLs for EtOH preference drinking. Ninety-four transcripts were detected as being differentially expressed in both selected lines versus HS controls; there was no overlap with known preference genes. The WGCNA revealed 2 modules as showing significant effects of both selections on intramodular connectivity. A number of genes known to be associated with EtOH phenotypes (e.g., Gabrg1, Glra2, Grik1, Npy2r, and Nts) showed significant changes in connectivity. Conclusions: We found marked and consistent effects of selection on coexpression patterns; DE changes were more modest and less concordant. The QTLs and differentially expressed genes detected here are distinct from the preference phenotype. This is consistent with behavioral data and suggests that the DID and preference phenotypes are markedly different genetically.

Original languageEnglish (US)
Pages (from-to)1295-1303
Number of pages9
JournalAlcoholism: Clinical and Experimental Research
Volume37
Issue number8
DOIs
StatePublished - Aug 2013

Fingerprint

Gene Regulatory Networks
Drinking
Brain
Genes
Phenotype
Electric network analysis
Gene expression
Gene Expression
Chromosomes, Human, Pair 16
Chromosomes, Human, Pair 14
Chromosomes, Human, Pair 4
Neurobiology
Quantitative Trait Loci
Transcriptome
Ethanol
Chromosomes
Blood

Keywords

  • Alcohol
  • Binge
  • Drinking in the Dark
  • Microarray
  • Mouse
  • Selection
  • Weighted Gene Coexpression Network Analysis

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Psychiatry and Mental health
  • Toxicology

Cite this

Selection for drinking in the dark alters brain gene coexpression networks. / Iancu, Ovidiu; Oberbeck, Denesa; Darakjian, Priscila; Metten, Pamela; McWeeney, Shannon; Crabbe, John Jr; Hitzemann, Robert.

In: Alcoholism: Clinical and Experimental Research, Vol. 37, No. 8, 08.2013, p. 1295-1303.

Research output: Contribution to journalArticle

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AU - Iancu, Ovidiu

AU - Oberbeck, Denesa

AU - Darakjian, Priscila

AU - Metten, Pamela

AU - McWeeney, Shannon

AU - Crabbe, John Jr

AU - Hitzemann, Robert

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N2 - Background: Heterogeneous stock (HS/NPT) mice have been used to create lines selectively bred in replicate for elevated drinking in the dark (DID). Both selected lines routinely reach a blood ethanol (EtOH) concentration (BEC) of 1.00 mg/ml or greater at the end of the 4-hour period of access in Day 2. The mechanisms through which genetic differences influence DID are currently unclear. Therefore, the current study examines the transcriptome, the first stage at which genetic variability affects neurobiology. Rather than focusing solely on differential expression (DE), we also examine changes in the ways that gene transcripts collectively interact with each other, as revealed by changes in coexpression patterns. Methods: Naïve mice (N = 48/group) were genotyped using the Mouse Universal Genotyping Array, which provided 3,683 informative markers. Quantitative trait locus (QTL) analysis used a marker-by-marker strategy with the threshold for a significant logarithm of odds (LOD) set at 10.6. Gene expression in the ventral striatum was measured using the Illumina Mouse 8.2 array. Differential gene expression and the weighted gene coexpression network analysis (WGCNA) were implemented largely as described elsewhere. Results: Significant QTLs for elevated BECs after DID were detected on chromosomes 4, 14, and 16; the latter 2 were associated with gene-poor regions. None of the QTLs overlapped with known QTLs for EtOH preference drinking. Ninety-four transcripts were detected as being differentially expressed in both selected lines versus HS controls; there was no overlap with known preference genes. The WGCNA revealed 2 modules as showing significant effects of both selections on intramodular connectivity. A number of genes known to be associated with EtOH phenotypes (e.g., Gabrg1, Glra2, Grik1, Npy2r, and Nts) showed significant changes in connectivity. Conclusions: We found marked and consistent effects of selection on coexpression patterns; DE changes were more modest and less concordant. The QTLs and differentially expressed genes detected here are distinct from the preference phenotype. This is consistent with behavioral data and suggests that the DID and preference phenotypes are markedly different genetically.

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