We have provided evidence for the involvement of α6 and β3 in nicotine dependence measured by DSM-IV in a population-representative sample, further supporting the results in the literature for association of dependence defined by the Fagerstrom Test for Nicotine Dependence (FTND) with these genes in selected samples (Bierut et al, 2007; Greenbaum et al, 2006; Saccone et al, 2007). Furthermore, in our secondary analysis using different subsets of the sample based on phenotype definition, we also showed that sample selection can greatly affect the ability to detect association. Given the collection of studies that have now provided evidence for an association between these genes and nicotine behaviors, it will be important for future studies to focus on understanding the molecular functional consequences of different SNPs. This should include work aimed at identifying all of the variation in the region, followed by in vitro and in vivo approaches to study the effects of these variants. Ultimately, it will take a careful integration of results from human genetic studies with laboratory based methods in order to tease apart the complex underlying genetic mechanisms which contribute to risk for nicotine dependence.
