In this study, we have taken a systematic approach to examine joint effects of variants marking the cholinergic nicotinic receptor subunit genes on smoking behavior. Nicotine dependence is a heritable behavior, with estimates of approximately 50% for the genetic contribution to phenotypic variance (Li et al. 2003; Sullivan and Kendler 1999). The α5α3β4 cholinergic nicotinic receptor cluster on chromosome 15 is now unequivocally associated with nicotine dependence and the number of cigarettes smoked per day (Amos et al. 2008; Berrettini et al. 2008; Bierut et al. 2007; Bierut et al. 2008; Liu et al. 2010; Saccone et al. 2009b; Saccone et al. 2007; Stevens et al. 2008; Thorgeirsson et al. 2010; Tobacco and Genetics Consortium 2010; Weiss et al. 2008). For example, a recent report of a meta-analysis with 76,972 subjects (Thorgeirsson et al. 2010) achieves a p value 2.4 × 10–69 for a SNP in this cluster. Other cholinergic nicotinic receptors play a more modest role (Saccone et al. 2010b; Schlaepfer et al. 2008; Thorgeirsson et al. 2010).
