Quantitative trait loci involved in genetic predisposition to acute alcohol withdrawal in mice

Kari Johnson Buck, Pamela Metten, John K. Belknap, John C. Crabbe

Research output: Contribution to journalArticle

235 Scopus citations

Abstract

Alcohol dependence (alcoholism) is accompanied by evidence of tolerance, withdrawal (physiological dependence), or compulsive behavior related to alcohol use. Studies of strain and individual differences using animal models for acute physiological dependence liability are useful means to identify potential genetic determinants of liability in humans. Behavioral and quantitative trait analyses were conducted using animal models for high risk versus resistance to acute physiological dependence. Using a two-step genetic mapping strategy, loci on mouse chromosomes 1, 4, and 11 were mapped that contain genes that influence alcohol withdrawal severity. In the aggregate, these three risk markers accounted for 68% of the genetic variability in alcohol withdrawal. Candidate genes in proximity to the chromosome 11 locus include genes encoding the α1, α6, and γ2 subunits of type-A receptors for the inhibitory neurotransmitter, GABA. In addition, suggestive linkage is indicated for two loci on mouse chromosome 2, one near Gad1 encoding glutamic acid decarboxylase, and the other near the E12 locus which influences the seizure phenotype in the neurological mutant strain EI. The present analyses detect and map some of the loci that increase risk to develop physiological dependence and may facilitate identification of genes related to the development of alcoholism. Syntenic conservation between human and mouse chromosomes suggests that human homologs of genes that increase risk for physiological dependence may localize to 1q21-q32, 2q24-q37/11p13, 9p21- p23/1p32-p22.1, and 5q32-q35.

Original languageEnglish (US)
Pages (from-to)3946-3955
Number of pages10
JournalJournal of Neuroscience
Volume17
Issue number10
StatePublished - May 22 1997

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Keywords

  • GABA(A) receptor
  • QTL
  • ethanol
  • glutamic acid decarboxylase
  • handling-induced convulsions
  • physiological dependence
  • quantitative trait locus
  • recombinant inbred strain
  • seizure
  • selective breeding
  • withdrawal

ASJC Scopus subject areas

  • Neuroscience(all)

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