Until very recently, candidate gene association studies have focused on genes in a few candidate pathways. A ‘reward deficiency syndrome’ has been postulated as one unifying theme to account for the role of diverse neurotransmitters in nicotine dependency [25], [26], [27], and consequently many studies have evaluated genes in opioid [28], [29], serotinergic [30], [31], [32], dopaminergic [26], [33], [34], [35], drug metabolizing enzyme [36], [37], [38], [39], [40], [41] and nicotinic and muscarinic cholinergic receptor pathways[42], [43]. Results from these studies have been largely equivocal, due to small sample sizes in individual studies, incomplete and non-overlapping genetic coverage, differences in measures of smoking behavior, or differences in genetic and environmental backgrounds. It is also highly probable that many of the loci that influence smoking behavior lie outside of the previously-studied candidate regions.
