The case for these two loci having a synergistic joint effect has been greatly strengthened by results very recently reported by the Consortium for the Genetic Analysis of Smoking Phenotypes (CGASP) (Saccone et al. 2010a). The CGASP subjects consist of current and former smokers of European ancestry (N = 38,617), including COGEND and ACS subjects. A case/control phenotype of heavy versus light smoking was analyzed. In univariate analysis, the locus tagged by rs16969968 was highly associated with the heavy smoking phenotype (p = 5.96 × 10–31), while the second locus, tagged by rs588765, was considerably less significant (p = 4.54 × 10–4). When the two loci were analyzed jointly, each became more significant: p = 3.52 × 10–36 for the locus tagged by rs16969968, and p = 6.03 × 10–9 (passing the threshold for genome-wide significance) for the locus tagged by rs588765. The logistic regression interaction term in this analysis was not significant. The explanation for these results is that the risk alleles for the two loci are negatively correlated. As a result, in a univariate analysis, the association of
