These studies focus on alleles associated with both risk for dependence as well as the number of cigarettes smoked per day, which are components of Stages 3 and 4 as outlined in Table 1. However, the human polymorphisms could also influence other stages as well (e.g., withdrawal and relapse). In contrast to the studies of OPRM1 discussed above, which follow up on polymorphism implicated by candidate gene studies, the CHRNA3-CHRNA5-CHRNB4 gene cluster was discovered by GWAS and is extremely statistically robust. Another contrast with the OPRM1 studies is that neither of these mouse models of nicotinic subunits introduced a particular human polymorphism into the mice. Thus, the data speak more to the importance of these nicotinic subunits and of the habenula rather than specific confirmation of the causal role of any particular polymorphism's importance in humans.
