While concerns about multiple testing apply in this exploratory work, there are several discoveries that warrant further discussion. The first and third top findings in this paper involved two weakly correlated SNPs from the GRIN2B gene; these were not detected under the main-effect model in the initial candidate gene study. This gene encodes subunits of the N-methyl-D-aspartate (NMDA) receptor channel, which appears be involved in mediating neural-plasticity leading to drug dependence (Kelley 2004; Hyman et al. 2006). Notably, the expression and subunit composition of NMDA receptors change markedly over the course of development, and NMDA-mediated neuroplasticity may be heightened in adolescence (Carpenter-Hyland and Chandler 2007; Lau and Zukin 2007). GRIN2B SNPs have been implicated in correlated phenotypes such as ADHD and alcohol-related traits (Wernicke et al. 2003; Dorval et al. 2007) and one very recent report provides strong evidence for an association between SNPs in this gene and smoking initiation (Vink et al. 2009). The results here suggest that GRIN2B polymorphisms may be important, age-dependent factors in the development of nicotine dependence. Based on both compelling biological evidence and association studies, the SNPs identified here and correlated polymorphisms warrant more detailed studies in this and other samples.
