The most significant finding (rs578776) has been associated with nicotine dependence in multiple independent samples and the minor allele confers a protective effect. Results of this meta-analysis suggest the protective effect imparted by the minor allele may influence early smoking behaviors, resulting in a decreased risk of nicotine dependence later in life. Perhaps even more interesting is the fact that there was absolutely no evidence at the most highly replicated locus for smoking heaviness (rs16969968), which has been shown to confer a functional effect on receptor function [Bierut et al., 2008; Fowler et al., 2011; Kuryatov et al., 2011]. This is the third study to report nonsignificance for age of initiation or age of onset of smoking at the rs16969968 [Furberg et al., 2010; Hartz et al., 2012; Thorgeirsson et al., 2010]. This work emphasizes the fact that early smoking behaviors are related to, but different from nicotine dependence. It also demonstrates the value in pursuing multiple SNPs in a region where one SNP has been definitively associated with behavior and has concomitant evidence for molecular function. It is likely
