It is unclear why the FTND item ��Can��t refrain from smoking�� showed www.selleckchem.com/products/BIBW2992.html the strongest association with rs6474412, but this could be related to its significant correlation with CPD (r = .59). The strongest association with rs6474412 was with the WISDM ��Tolerance�� scale, which comprises items, such as ��I consider myself a heavy smoker,�� again affirming that rs16969968 and rs6474412 are associated with overlapping domains of nicotine dependence characterized by heavy smoking. Before the biological mechanisms are clarified for CHRNA5 and CHRNB3, the possibility of having distinct but related phenotypes with these two variants cannot be ruled out. The third variant, rs3733829 in the EGLN2 gene about 40 kb from the 3�� end of CYP2A6, showed a modest association with nicotine dependence.

When the genetic association was modest, we were unable to differentiate the degree of association based on the different phenotypic definitions. Our data do not support the previously reported association with rs1329650 on chromosome 10. Most nicotine dependence phenotypes showed no evidence of association (p > .50). Though DSM-IV nicotine dependence demonstrated a weak association, the effect was in the opposite direction from what was previously reported; thus, our results must be interpreted as nonreplication (TAG, 2010). Based on the allele frequency and our sample size, our study has sufficient power to detect an association with OR of 1.14 or higher (Gauderman & Morrison, 2006). There are several limitations to our study.

Our sample selection for cases and controls was based on extreme FTND scores, so a comparison Brefeldin_A of FTND results with the other nicotine dependence phenotypes cannot be directly made. We purposely examined the strength of genetic associations within FTND measures as one set of analyses. In a separate analysis, we examined the level of genetic association among other nicotine dependence phenotypes (DSM-IV, DSM-V, NDSS, and WISDM). In order to adjust for the ascertainment bias that was built into our study design, we performed additional analyses correcting for the bias (Lin & Zeng, 2009) and obtained similar results. Second, caution is needed in interpreting these intertwined clinical constructs. There is moderate to high correlation among the examined phenotypes and subphenotypes. As a consequence, the pattern of significant findings can be somewhat misleading. For instance, the DSM ��Craving�� item has a significant stepwise association with rs16969968, but the WISDM ��Craving�� item did not (instead, the WISDM ��Loss of Control�� subscale was significant in the stepwise tests). In fact, both craving measures are similarly highly associated with rs16969968 as indicated by their CIs (Table 4), suggesting no real inconsistency.