In our European-American population, we did not find evidence of significant associations (P<0.05 in early or late onset smokers) among the four CHRNA4 SNPs in common with our study (rs2273504, rs2236196, rs1044396, rs1044397; Table S3) and previous candidate gene association studies of nicotine dependence in Chinese men [5], and females of European-American and African-American descent [6]. A follow-up candidate gene study [9] to a genome-wide association design [8] with a definition of no dependence (FTND = 0) in controls and a FTND>3 for dependence in cases of European descent, identified significant associations within CHRNB3 and the CHRNA5-A3-B4 cluster. Although that study [9] and the current study employed tagging SNPs for similar LD bins, the current study did not find any association between nicotine dependence and CHRNB3 SNPs. However, similar LD bins within the CHRNA5-A3-B4 cluster showed a significant risk effect in both studies, including the nonsynonymous α5 rs16969968 SNP, even with the substantial difference in FTND criteria. Using similar criteria for low and high dependence as our study, a previous study [7] also reported a suggestive association (primary P =
