By extending the tested genomic region from genes to pathways - where a pathway is a ‘meta-gene’ comprising multiple genes having the same biological function – we identified chains of pathways statistically associated with ever smoking and quantity smoked (see Supplementary Figures 42). The strongest association signal in the quantity smoked analysis was yielded by the highly calcium permeable postsynaptic nicotinic acetylcholine receptors pathway (P=4.90E-42) harboring the nicotinic acetylcholine receptors. The results are consistent with the hypothesis that mechanisms underlying smoking dependence involve the mesocorticolimbic dopamine system 10, 43. In short, as Benowitz described 44, the biological mechanisms underlying nicotine addiction involve nicotine binding to the nicotinic acetylcholine receptors which, in turn, release several neurotransmitters (dopamine, glutamate and γ-aminobutyric acid) in regions of the brain known to be involved in the perception of pleasure and reward (i.e., in the ventral tegmental area and the shell of the nucleus acumbens). Following repeated exposure, the nicotinic acetylcholine receptors adapt to nicotine and become unresponsive. It is hypothesized that the reactivation of these closed receptors following abstinence/cessation gives rise to symptoms of craving
