In conclusion, this work replicates an association between variations in the CHRNB3 gene promoter region and “dizziness” sensations during early tobacco use. Functional data using reporter-gene assays support the hypothesis that different alleles of SNPs upstream of CHRNB3 may lead to differential RNA expression of the gene. In addition, we have found modest evidence for an association between CHRNA4 and “dizziness” and strong evidence for an association with CHRNA10. These findings provide important insight into the developmental trajectory for nicotine dependence, and the utility of focusing on an early tobacco response phenotype in genetic studies. This idea was described in a theoretical framework of the neuroregulatory effects of nicotine by Pomerleau and colleagues over twenty years ago (Pomerleau and Pomerleau, 1984). In the current study, subjects were asked retrospectively about their early responses to cigarettes, and the potential for inaccurate recall is a major limitation. In the Zeiger et al. (2008) study, two different young adult samples were assessed within 5–10 years of their initiation, so the convergence across the three samples suggests this phenotype is likely to be important.
