In contrast to candidate gene and pathway-based approaches, genome-wide association studies (GWAS) are hypothesis-free and seek to identify loci for novel susceptibility genes. Such approaches have discovered genetic variants in the α5/α3/β4 nAChR gene cluster as associated with nicotine dependence and heaviness of smoking (Berrettini et al. 2008; Bierut et al. 2008; Thorgeirsson and Stefansson 2008). These genes have attracted a significant amount of attention and the associations with smoking heaviness are robust and important. However, studies attempting to confirm associations of these SNPs with retrospective and prospective smoking cessation have yielded mixed results (Breitling et al. 2009a; Greenbaum and Lerer 2009; Ray et al. 2010). While GWAS is a very useful approach, genetic variants identified via GWAS account for a very small proportion of the variance in smoking behavior (<5%), and thus, the clinical utility of these results is not yet clear (Furberg et al. 2010). To date, few GWAS studies of smoking cessation have been conducted (Uhl et al. 2007) in part due to the need for larger sample sizes than may be feasible to acquire from clinical
