title: Gamma-aminobutyric acid receptor genes and nicotine dependence: evidence for association from a case-control study.
abstract: OBJECTIVE
  The gamma-aminobutyric acid receptor A (GABRA) gene clusters on chromosomes 4 and 5 have been examined previously for their association with alcohol and drug dependence phenotypes. Compelling evidence suggests that GABRA2 is associated with alcohol and drug dependence. However, no study has investigated whether genes in the GABA(A) gene clusters are associated with nicotine dependence, an important phenotype with a high correlation to persistent smoking, the single most preventable cause of mortality world-wide.
  
  
  METHODS
  Using data on 1050 nicotine-dependent cases and 879 non-dependent smoking controls, we used logistic regression to examine the association between single nucleotide polymorphisms (SNPs) in 13 genes in the GABA(A) receptor system as well as GABBR2 (a GABA(B) gene).
  
  
  RESULTS
  We found evidence for association between four SNPs in GABRA4, two SNPs in GABRA2 and one SNP in GABRE with nicotine dependence. These included a synonymous polymorphism in GABRA2 (rs279858), lying in a highly conserved region, which has been shown previously to be associated with alcohol and drug dependence. A non-synonymous polymorphism (rs16859834/rs2229940) in GABRA4, also highly conserved, was associated at P-value of 0.03. Significant haplotypes associated with nicotine dependence were found for GABRA2. No evidence for epistatic interactions were noted. Our study did not find evidence for an association between GABBR2 gene and nicotine dependence.
  
  
  CONCLUSIONS
  Given the potential role of compounds that enhance GABAergic neurotransmission in smoking cessation research, these findings have enormous potential for informing the wider field of addiction research.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, USA. arpana@wustl.edu
authors.forename: Arpana
authors.initials: A
authors.lastname: Agrawal
authors.forename: Michele L
authors.initials: ML
authors.lastname: Pergadia
authors.forename: Scott F
authors.initials: SF
authors.lastname: Saccone
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Hinrichs
authors.forename: Christina N
authors.initials: CN
authors.lastname: Lessov-Schlaggar
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Saccone
authors.forename: Rosalind J
authors.initials: RJ
authors.lastname: Neuman
authors.forename: Naomi
authors.initials: N
authors.lastname: Breslau
authors.forename: Eric
authors.initials: E
authors.lastname: Johnson
authors.forename: Dorothy
authors.initials: D
authors.lastname: Hatsukami
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Heath
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.forename: John P
authors.initials: JP
authors.lastname: Rice
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Bierut
authors.forename: Pamela A F
authors.initials: PA
authors.lastname: Madden
mesh_terms: D016739:Behavior, Addictive / Q000235:genetics*; D016022:Case-Control Studies; D002905:Chromosomes, Human, 4-5; D019317:Evidence-Based Medicine; D005260:Female; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D010641:Phenotype; D018079:Receptors, GABA / Q000235:genetics* / Q000378:metabolism; D016540:Smoking Cessation / Q000379:methods; D014029:Tobacco Use Disorder / Q000235:genetics*
chemical_list: D018079:Receptors, GABA