Single- and Multilocus Allelic Variants within the GABAB Receptor Subunit 2 (GABAB2) Gene Are Significantly Associated with Nicotine Dependence


Twelve single-nucleotide polymorphisms (SNPs) in the human γ-aminobutyric acid type B (GABAB) receptor subunit 2 gene (GABAB2) were tested for association with nicotine dependence (ND) in an extensively phenotyped cohort of 1,276 smokers and nonsmokers, representing ≃404 nuclear families of African American (AA) or European American (EA) origin. The GABAB2 gene encodes a subunit of the GABAB receptor for GABA, an inhibitory neurotransmitter involved in the regulation of many physiological and psychological processes in the brain. The gene is located within a region of chromosome 9q22 that showed a "suggestive" linkage to ND. Individual SNP analysis performed using the PBAT-GEE program indicated that two SNPs in the AAs and four SNPs in the EAs were significantly associated with ND. Haplotype analysis using the Family-Based Association Test revealed that, even after Bonferroni correction, the haplotype C-C-G of rs2491397-rs2184026-rs3750344 had a significant positive association with ND in both the pooled and the AA samples. In the EAs, we identified two haplotypes, C-A-C-A and T-A-T-A, formed by SNPs rs1435252-rs378042-rs2779562-rs3750344, that showed a highly significant negative and positive association with ND, respectively. In summary, our findings provide evidence of a significant association of GABAB2 variants with ND, implying that this gene plays an important role in the etiology of this drug addiction. © 2005 by The American Society of Human Genetics. All rights reserved.

Publication Title

American Journal of Human Genetics