The dopaminergic system has long been acknowledged to play a critical role in nicotine addiction.40 The most studied gene in this system is DRD2, located on chromosome 11q23.2 within a modest linkage peak.41 The intriguing polymorphism Taq1A is located in ANKK1 near DRD2, leading to an amino acid change in ANKK1.42 Several other variants and haplotypes in regions adjacent to DRD2, within TTC12 and ANKK1, or downstream of DRD2 have been associated with smoking-related phenotypes.13, 43-47 Besides DRD2, a modest number of studies have shown significant associations between ND traits and other dopamine receptor genes, such as DRD148 and DRD4,49-51 and genes involved in dopamine metabolism, including dopamine β-hydroxylase (DBH),13, 52, 53 DOPA decarboxylase (DDC),54, 55 and catechol-O-methyl transferase (COMT).56-61 All of these genes are within or close to the nominated linkage peaks34 except for DBH and DDC, which have received support from GWAS results16 and as ND-associated genes from two independent studies with sample sizes ≥ 1,000.13,50-53
