who have never used would develop dependence if exposure occurred. Consistent with this observation, the recent successes in addiction genetics have been in studies focusing on variation within drug-exposed populations or included controls with significant exposure (Cornelis et al., 2011; Sulem et al., 2011; Tobacco and Genetics Consortium, 2010). In genetic studies of tobacco addiction (e.g., (S. F. Saccone et al., 2007; Tobacco and Genetics Consortium, 2010), the importance of using screened controls is highlighted. Using a very large sample (N=143,023), Tobacco and Genetics Consortium researchers performed a genome-wide association scan, or tests of association between approximately one million SNPs genome-wide, and phenotypes of smoking including age of initiation, use and cessation, with minimal success. In a smaller sample restricted to smokers (N=73,853) for smoking quantity, a highly significant association of characteristics of smoking with the nicotinic acetylcholine receptor gene cluster (CHRNA5-A3-B4) on chromosome 15 was replicated. In prior studies, similar results had been found using controls who were limited to smokers who had not become dependent (N. L. Saccone et al., 2010). It is believed that specific variants in these loci confer elevated risk to nicotine dependence after commencing smoking via differences in corticostriatal response to nicotine (Janes et
