level for the type of hypothesis of interest. Since the genes were chosen to capture the important components within the entire system, we use a conservative significance α-level of 0.0009 across the 54 gene regions to indicate significance at the system-level. We did not adjust the P-values in our presentation because we believe a transparent presentation of the results is necessary to emphasize associations that are consistent with previous knowledge and to highlight the need for replication of unexpected results. For example, several additional genes (TDO2, ADCYAP1, HTR1B, CDK5, and FOSB) have at least one SNP achieving an adjusted P-value of <0.05, but they are not significant at the systems level. These genes are still of interest as there are varying amount of prior evidence for each (50–53). In addition, there are several recent reports of genes (e.g. DRD1, DRD2, DRD3, ANKK1, BDNF, and NTRK2) within the dopamine system being involved in nicotine dependence (13,54–56). While there are some SNPs within these genes that have observed P-values <0.05 (e.g. DRD1 and DRD2) in the current study, none of these genes have SNPs with significantly adjusted P-values. Furthermore, none of the reported SNPs are significant in the current study (see Supplementary
