(Asn) allele decreases response to a nicotine agonist [Bierut et al., 2008]. The high-risk α5 Asn 398 is associated with reduced Ca2+ permeability and desensitizes faster than the wild type Aspartic acid (Asp) at 398 (α4β2)2 α5 [Kuryatov et al., 2011]. In addition, Alpha5 knockout mice showed increased nicotine intake [Fowler et al., 2011]. This variant accounts for 4% of the variance in the serum levels of the long-term metabolite of nicotine, cotinine [Etter et al., 2009; Keskitalo et al., 2009]. In addition to this well-characterized functional variant, there have been other robust associations within the CHRNA5/CHRNA3/CHRNB4 gene cluster to smoking quantity. These were reported in three genome-wide meta-analyses identifying SNPs in the cluster as top association signals with the outcome of cigarettes smoked per day (CPD) [Furberg et al., 2010; Liu et al., 2010; Thorgeirsson et al., 2010]. These reports support the prevailing view that smoking quantity/frequency as a proxy for nicotine dependence is most consistently associated with SNPs at the CHRNA5/CHRNA3/CHRNB4 locus. A fourth meta-analysis [Saccone et al., 2010a] focused on four statistically distinct loci in the CHRNA5/CHRNA3/CHRNB4 cluster tagged by SNPs rs16969968 (CHRNA5), rs578776 (CHRNA3), rs588765 (CHRNA5), and rs12914008 (CHRNB4) [Saccone et al., 2009a]. SNPs rs16969968 and
