Further evidence for an association between the gamma-aminobutyric acid receptor A, subunit 4 genes on chromosome 4 and Fagerstrom Test for Nicotine Dependence

A previous association analysis identified polymorphisms in gamma-aminobutyric acid receptor A, subunit 4 (GABRA4) and GABRA2 to be associated with nicotine dependence, as assessed by a score of 4 or more on the Fagerstrom Test for Nicotine Dependence (FTND). In the present report, we extend the previous study by expanding our genotyping efforts significantly for these two genes. In 1049 cases (FTND of 4 or more) and 872 controls (smokers with FTND of 0) from the United States and Australia, we examine the association between 23 GABRA4 and 39 GABRA2 recently genotyped single nucleotide polymorphisms (SNPs) and nicotine dependence using logistic regression-based association analyses using the genomic analysis package PLINK. Two and 18 additional SNPs in GABRA4 and GABRA2, respectively, were associated with nicotine dependence. The SNPs identified in GABRA4 (P-value = 0.002) were restricted to introns 1 and 2, exon 1 and the 5' end of the gene, while those in GABRA2 localized to the 3' end of the gene and spanned introns 9-3, and were in moderate to high linkage disequilibrium (as measured by r(2)) with each other and with previously studied polymorphisms. Our findings demonstrate consistently the role of GABRA4 and GABRA2 in nicotine dependence. However, further research is needed to identify the biological influence of these intronic variations and to isolate functionally relevant polymorphisms neighboring them.