19�C0.77), but there was no significant diplotype effect in the selleck chem inhibitor late-onset condition (see Figure 2). A post-hoc analysis in the early-onset condition, in which diplotype AB was the reference condition, indicated a significant AB versus BC effect, p=.001, OR=0.37 (95% CI=0.20�C0.67). With continuous scoring of PDM, there was a diplotype effect in early-onset smokers, F(4, 376)=2.36, p=.05. There were nonsignificant trends in the early-onset condition for diplotype BC (M=4.6, SD=1.5) to be associated with lower PDM scores than either AA (M=5.2, SD=1.3), p=.06, or AB (M=5.1, SD=1.3), p=.07. There was no diplotype effect in late-onset smokers. Overall, these findings suggest that HA and HC exert relative risk and protective effects, respectively, on heavy, automatic, and pervasive smoking in early-onset smokers.

We also examined the associations of individual PDM scales with genetic variants to shed light on the features of heavy, pervasive smoking that are most sensitive to the CHRNA5-A3-B4 genetic signal. We analyzed the associations between dichotomous scoring of each of the four constituent PDM scales and both haplotypes and diplotypes among early-onset smokers. The strongest haplotype signals were obtained with the Tolerance scale (see Figure 3). HA was associated with higher Tolerance scores than either HB, p<.01, OR=0.65 (95% CI=0.48�C0.89), or HC, p=9��10?5, OR=0.47 (95% CI=0.32�C0.68). Similar but slightly weaker signals were obtained with Craving: HA versus HB, p<.04, OR=0.71 (95% CI=0.52�C0.96); and HA versus HC, p<.03, OR=0.64 (95% CI=0.44�C0.93).

Although there was a trend for HA to be associated with higher Automaticity and Loss of Control scores than was HC, we found no significant haplotype effects for either of these scales. The Tolerance scale also was strongly associated with diplotypes (see Figure 3). Diplotype AA was associated with higher Tolerance scores than either BB, p=0.03, OR=0.44 (95% CI=0.21�C0.94), or BC, p=.001, OR=0.29 (95% CI=0.14�C0.60). For the Craving scale, AA was associated with higher scores than BB, p=.04, OR=0.46 (95% CI=0.22�C0.95), and there was a nonsignificant trend for AA to be associated with higher scores than BC, p=.07, OR=52 (95% CI=0.26�C?1.04). Consistent with the findings for Tolerance and Craving, diplotype AA was associated with higher Loss of Control scores than was BB, p=.004, OR=0.35 (95% CI=0.

17�C0.71). Diplotype AA also was associated with higher scores on Loss of Control than was AB, p=.05, OR=0.53 (95% CI=0.28�C1.00). Automaticity was not associated with the diplotypes. Figure 3. Dichotomous Primary Dependence Motives scales by haplotype (top) and diplotype (bottom) in early-onset smokers. The scales AV-951 were scored dichotomously based on the median for both age-at-onset conditions. To assess the robustness of the PDM findings across cohorts, haplotype associations with dichotomized PDM and Tolerance (i.e.