In summary, our study confirms the previously reported genetic association between CHRNA4 polymorphisms and smoking behavior in independent samples of AAs and EAs. Although rs2236196 could be one of the causal variants for smoking behavior, other independently associated functional variants, especially rare variants, may have been missed due to the limitations of the current study design. To identify the full range of CHRNA4 variants and to evaluate their role in smoking behavior, complete sequencing of the gene is necessary.