However, even given that, this study shows that the key rs16969968 and rs6474412 genetic variants were reliably associated only with certain types of dependence measures: those reflecting heavy out-of-control smoking accompanied by strong craving. For none of the genetic selleck Ganetespib variants were the associations of the WISDM SDM scales as strong as those for the PDM scales. Another limitation is that only selected genetic variants were tested. These variants were identified in several large Genome-Wide Association Studies (GWAS) of smoking, which have used the simple measure of CPD as the primary phenotype (Liu et al., 2010; TAG, 2010; Thorgeirsson et al., 2010). These variants were selected on the basis of their prior associations with CPD, so our finding of CPD as one of the strongest association findings may be the result of a bias based on the original phenotype that identified these variants.

The more comprehensive measures of nicotine dependence are not widely available in genetic samples, and no GWAS has been performed on the WISDM or NDSS. Until GWAS using these other phenotypic definitions is performed, we will not be able to determine if there are additional novel variants associated with these other phenotypes to be identified. Finally, our goal was to examine phenotype�Cgenotype relations by comparing the genetic associations across phenotypes and characterizing the subphenotypes�� best capturing known genetic associations. This work informs our understanding of phenotypes and the mission to improve diagnostic validity.

For example, a proposed test of the validity of mental disorder diagnosis for DSM-V includes identified genetic risk factors (Carpenter et al., 2009). If biological or genetic factors are an important test of the validity of mental disorder diagnosis, this evidence suggests the importance of measuring smoking heaviness and ��Craving�� to reflect part of the underlying genetic risk. Though the variance explained by these genetic polymorphisms is small (2.4% by four variants for FTND), the current evidence suggests that measures of smoking heaviness, in particular, the number of cigarettes smoked per day, is an important measure of nicotine dependence that captures part of the genetic variance related to nicotine dependence. Adding ��Craving�� as a symptom criterion in DSM-V is supported in our work.

Although CPD is a simple measure from a psychiatric or psychological perspective, it is an important measure used in medicine because it assesses the toxic exposure from smoking, which is a determinant of diseases, such as lung cancer and chronic obstructive pulmonary disease. Therefore, we suggest Batimastat that CPD be considered in the future assessment of nicotine use disorders, including DSM-V. Supplementary Material Supplementary Tables 1�C4 can be found online at http://www.ntr.oxfordjournals.