title: Association of GABRG3 with alcohol dependence.
abstract: BACKGROUND
  Evidence from human, animal, and in vitro cell models suggests that gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the human central nervous system, is involved in many of the neurochemical pathways that affect alcohol use, abuse, and dependence. Both linkage and association to the region on chromosome 15q that contains a cluster of GABAA receptor genes have previously been reported, but the role of these genes in alcoholism remains inconclusive.
  
  
  METHODS
  We conducted family-based association analyses by using a large sample of multiplex alcoholic families collected as part of the Collaborative Study on the Genetics of Alcoholism, to test for an association between alcohol dependence and the GABAA receptor genes clustered on chromosome 15q. Multiple single-nucleotide polymorphisms were tested in each of the three chromosome 15q GABAA receptor genes: GABRA5, GABRB3, and GABRG3.
  
  
  RESULTS
  Using both classic trio-based analyses and extended-family analyses, we found consistent evidence of association between alcohol dependence and GABRG3. Nearly all single-nucleotide polymorphisms across the gene yielded evidence of association, and haplotype analyses were highly significant. No consistent evidence of association was observed with either GABRA5 or GABRB3, nor was there evidence for parent-of-origin effects with any of the genes.
  
  
  CONCLUSIONS
  These analyses suggest that GABRG3 may be involved in the risk for alcohol dependence. These findings support the theory that the predisposition to alcoholism may be inherited as a general state of central nervous system disinhibition/hyperexcitability that results from an altered responsiveness to GABA.
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Dick
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Edenberg
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xuei
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.forename: Sam
authors.initials: S
authors.lastname: Kuperman
authors.forename: Marc
authors.initials: M
authors.lastname: Schuckit
authors.forename: Raymond
authors.initials: R
authors.lastname: Crowe
authors.forename: Tom L
authors.initials: TL
authors.lastname: Smith
authors.forename: Bernice
authors.initials: B
authors.lastname: Porjesz
authors.forename: Henri
authors.initials: H
authors.lastname: Begleiter
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
mesh_terms: D000437:Alcoholism / Q000235:genetics*; D016009:Chi-Square Distribution; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D011110:Polymorphism, Genetic / Q000235:genetics; D011963:Receptors, GABA-A / Q000235:genetics*
chemical_list: D011963:Receptors, GABA-A