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Previous studies have demonstrated that the γ-aminobutyric acid type B (GABA B ) receptor plays an essential role in modulating neurotransmitter release and regulating the activity of ion channels and adenyl cyclase. However, whether the naturally occurring polymorphisms in the two GABA B  receptor subunit genes interact with each other to alter susceptibility to nicotine dependence (ND) remains largely unknown. In this study, we genotyped 5 and 33 single nucleotide polymorphisms (SNPs) for GABA B  receptor subunit 1 and 2 genes ( GABBR1, GABBR2 ), respectively, in a sample of 2037 individuals from 602 nuclear families of African- American (AA) or European-American (EA) origin. We conducted association analyses to determine (1) the association of each subunit gene with ND at both the individual SNP and haplotype levels and (2) the collective effect(s) of SNPs in both GABA B  subunits on the development of ND. Several individual SNPs and haplotypes in  GABBR2  were significantly associated with ND in both ethnic samples. Two haplotypes in AAs and one haplotype in EAs showed a protective effect against ND, whilst two other haplotypes in AAs and three haplotypes in EAs showed a risk effect for developing ND. Interestingly, these significant haplotypes were confined to two regions of  GABBR2  in the AA and EA samples. Additionally, we found two minor haplotypes in  GABBR1  to be positively associated with Heaviness of Smoking Index (HSI) in the EA sample. Finally, we demonstrated the presence of epistasis between  GABBR1  and  GABBR2  for developing ND. The variants of  GABBR1  and  GABBR2  are significantly associated with ND, and the involvement of  GABBR1  is most likely through its interaction with  GABBR2 , whereas  GABBR2  polymorphisms directly alter susceptibility to ND. Future studies are needed with more dense SNP coverage of  GABBR1  and  GABBR2  to verify the epistatic effects of the two subunit genes.

Association and Interaction Analyses of GABBR1 and GABBR2 with Nicotine Dependence in European- and African-American Populations