title: A GABRA2 variant is associated with increased stimulation and 'high' following alcohol administration.
abstract: OBJECTIVE
  Variation in genes encoding GABAA receptor subunits has been implicated in the risk of alcohol dependence (AD). We sought to replicate and extend previous findings of a moderating effect of single nucleotide polymorphisms (SNPs) in GABRA2 (which encodes the GABAA α-2 subunit) on the subjective effects of alcohol by examining SNPs in this and the adjacent GABRG1 gene on chromosome 4.
  
  
  METHODS
  Fifty-two European-Americans (22 males, 28 light drinkers and 24 heavy drinkers) completed 3 laboratory sessions, during which they drank low-dose, high-dose, or placebo alcohol prior to undergoing periodic assessments of stimulation, sedation and drug enjoyment. We genotyped subjects for three SNPs previously associated with AD: rs279858 in GABRA2, and rs7654165 and rs6447493 in GABRG1.
  
  
  RESULTS
  Two SNPs were associated with altered stimulatory effects of alcohol as measured on the Biphasic Alcohol Effects Scale, (rs279858: P = 0.0046; rs6447493: P = 0.0023); both effects were in the opposite direction of previous findings. Carriers of the rs279858 C allele experienced greater stimulation from alcohol. Further inspection of the rs6447493 interaction did not support a pharmacogenetic effect. The effects of rs279858 (but not the other two SNPs) on items from a secondary outcome measure, the Drug Effects Questionnaire (DEQ), were significant. Higher ratings by individuals with the C allele were observed on the DEQ items 'feel the alcohol effect' (P < 0.001), 'like the alcohol effect' (P < 0.001) and feel 'high' (P < 0.001).
  
  
  CONCLUSIONS
  We did not find that the GABRG1 SNPs rs7654165 and rs6447493 moderated the effects of alcohol. Greater stimulatory and euphoric effects of alcohol in carriers of the rs279858 C allele may, in part, explain the previously reported association of this allele with AD.
authors.affiliation: Corresponding author: Department of Psychiatry, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1410, USA. jocovault@uchc.edu.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Arias
authors.forename: Jonathan
authors.initials: J
authors.lastname: Covault
authors.forename: Richard
authors.initials: R
authors.lastname: Feinn
authors.forename: Timothy
authors.initials: T
authors.lastname: Pond
authors.forename: Bao-Zhu
authors.initials: BZ
authors.lastname: Yang
authors.forename: Wenjing
authors.initials: W
authors.lastname: Ge
authors.forename: Cheryl
authors.initials: C
authors.lastname: Oncken
authors.forename: Henry R
authors.initials: HR
authors.lastname: Kranzler
mesh_terms: D000328:Adult; D000339:Affect / Q000187:drug effects* / Q000502:physiology; D000428:Alcohol Drinking / Q000235:genetics* / Q000523:psychology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011963:Receptors, GABA-A / Q000235:genetics*; D055815:Young Adult
chemical_list: C484841:GABRA2 protein, human; D011963:Receptors, GABA-A; D000431:Ethanol