Human Molecular Genetics Advance Access originally published online on March 24, 2005
Human Molecular Genetics 2005 14(9):1211-1219; doi:10.1093/hmg/ddi132
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Ethnic- and gender-specific association of the nicotinic acetylcholine receptor 
4 subunit gene (CHRNA4) with nicotine dependence
1Program in Genomics and Bioinformatics on Drug Addiction, Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA, 2The ACT Tobacco Center, University of Mississippi Medical Center, Jackson, MS, USA and 3Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA
* To whom correspondence should be addressed at: MSC 7792, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. Tel: +1 2105670830; Fax: +1 2105670853; Email: lim2{at}uthscsa.edu
Received January 24, 2005; Accepted March 13, 2005
We tested six single nucleotide polymorphisms (SNPs) in the 
4 subunit gene (CHRNA4) and four SNPs in the ß2 subunit gene (CHRNB2) of nicotinic acetylcholine receptors (nAChRs) for association with nicotine dependence (ND), which was assessed by smoking quantity (SQ), the heaviness of smoking index (HSI) and the Fagerström test for ND (FTND) in 2037 subjects from 602 nuclear families of either European-American (EA) or African-American (AA) ancestry. Analysis of the six SNPs within CHRNA4 demonstrated that in the EA sample SNPs rs2273504 and rs1044396 are significantly associated with the adjusted SQ and FTND score, respectively. In the AA samples, SNPs rs3787137 and rs2236196 are each significantly associated with at least two adjusted ND measures. Association of rs2236196 with the adjusted HSI and FTND scores in the AA samples remained significant after correction for multiple testing. Furthermore, analysis revealed gender- and ethnic-specific associations for several SNPs with ND measures in both ethnic samples; however, only the association of SNP rs2236196 with the three adjusted ND measures remained significant after correcting for multiple testing in the AA female samples. Haplotype analysis of rs2273505–rs2273504–rs2236196 showed significant association after Bonferroni correction of a C–G–G haplotype (53.4%) with three adjusted ND measures in samples from the AA females. A similar analysis for the four SNPs within CHRNB2 did not reveal significant association with the three ND measures. In summary, our findings provide convincing evidence for the involvement of the nAChR 4 subunit, but not of the nAChR ß2 subunit, in nicotine addiction.
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