title: Identification of quantitative trait loci and candidate genes for an anxiolytic-like response to ethanol in BXD recombinant inbred strains.
abstract: Genetic differences in acute behavioral responses to ethanol contribute to the susceptibility to alcohol use disorder and the reduction of anxiety is a commonly reported motive underlying ethanol consumption among alcoholics. Therefore, we studied the genetic variance in anxiolytic-like responses to ethanol across the BXD recombinant inbred (RI) mouse panel using the light-dark transition model of anxiety. Strain-mean genetic mapping and a mixed-model quantitative trait loci (QTL) analysis replicated several previously published QTL for locomotor activity and identified several novel anxiety-related loci. Significant loci included a chromosome 11 saline anxiety-like QTL (Salanq1) and a chromosome 12 locus (Etanq1) influencing the anxiolytic-like response to ethanol. Etanq1 was successfully validated by studies with BXD advanced intercross strains and fine-mapped to a region comprising less than 3.5 Mb. Through integration of genome-wide mRNA expression profiles of the mesocorticolimbic reward circuit (prefrontal cortex, nucleus accumbens and ventral midbrain) across the BXD RI panel, we identified high priority candidate genes within Etanq1, the strongest of which was Ninein (Nin), a Gsk3β-interacting protein that is highly expressed in the brain.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Putman
authors.affiliation: Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Wolen
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Harenza
authors.affiliation: Institute of Mathematics and Informatics, Bulgarian Academy of Science, Sofia, Bulgaria.
authors.forename: R K
authors.initials: RK
authors.lastname: Yordanova
authors.affiliation: Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: B T
authors.initials: BT
authors.lastname: Webb
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME.
authors.forename: E J
authors.initials: EJ
authors.lastname: Chesler
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.|Department of Neurology, Virginia Commonwealth University, Richmond, VA, USA.|Center for Study of Biological Complexity, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Miles
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics*; D019973:Alcohol-Related Disorders / Q000235:genetics*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D002874:Chromosome Mapping; D000431:Ethanol / Q000494:pharmacology*; D056726:Genetic Association Studies; D014644:Genetic Variation; D008297:Male; D051379:Mice; D040641:Quantitative Trait Loci
chemical_list: D014151:Anti-Anxiety Agents; D000431:Ethanol
keywords: Anxiety; BXD recombinant inbred; Ninein; QTL; ethanol; microarray