Gamma-aminobutyric acid receptor genes and nicotine dependence: evidence for association from a case-control study.
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.
Agrawal
Arpana
A
Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, USA. arpana@wustl.edu
Pergadia
Michele L
ML
Saccone
Scott F
SF
Hinrichs
Anthony L
AL
Lessov-Schlaggar
Christina N
CN
Saccone
Nancy L
NL
Neuman
Rosalind J
RJ
Breslau
Naomi
N
Johnson
Eric
E
Hatsukami
Dorothy
D
Montgomery
Grant W
GW
Heath
Andrew C
AC
Martin
Nicholas G
NG
Goate
Alison M
AM
Rice
John P
JP
Bierut
Laura J
LJ
Madden
Pamela A F
PA
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*
D018079:Receptors, GABA