For the GABAergic system, variants in the GABAB receptor subunit 2 (GABBR2),73 GABAA receptor-associated protein (GABARAP),74 and GABAA receptor subunits alpha-2 (GABRA2) and −4 (GABRA4)13, 75, 76 were significantly associated with different ND phenotypes. Cui et al.77 reviewed the significance of the GABAergic system in ND and alcohol dependence. In addition, the serotonergic system is implicated in susceptibility to ND because nicotine increases serotonin release in the brain, and symptoms of nicotine withdrawal are associated with diminished serotonergic neurotransmission.78 Genes encoding serotonin receptor 3A, ionotropic (HTR3A),79 5A, G protein-coupled (HTR5A),13 and serotonin transporter (SLC6A4)80-82 showed significant association with smoking-related behaviors. All of these seven genes of the GABAergic and serotonergic systems are within or close to the nominated linkage peaks,34 which strengthens the validity of the identified associations, although two studies reported negative results for association between serotonin transporter gene (SLC6A4) and smoking behaviour.83, 84 Another gene worth mentioning for this group is serotonin receptor 2A, G protein-coupled (HTR2A), which is within a modest linkage peak (13q14) suggested by Li et al.85 and was significantly associated with smoking status in a Brazilian sample of 625 subjects.86 Replication in larger samples is needed to confirm association of this gene with ND.
