of neuromodulators or the rewarding efforts of nicotine on the mesolimbic system (24). Candidate gene studies investigated associations between measures of cigarette use initiation, intensity, and dependence and genes involved with nicotine receptors, dopaminergic transmission, and serotonin transporters. Despite some regions showing suggestive linkage in multiple studies, results have been heterogeneous. Added to this, genes implicated in candidate gene studies have not been reliably associated with cigarette use phenotypes in larger GWAS, the effects of most candidate genes for cigarette use remain largely ambiguous. Replication of candidate gene studies remains a problem because of small sample sizes in each individual study, differences in measures of cigarette use, and differences in genetic and environmental backgrounds (25). GWAS simultaneously analyzes common genetic variants across the entire genome and has have been used since the early 2000s to identify genetic variants contributing to cigarette use phenotypes (26). Gene-finding efforts have identified associations between a variety of cigarette use phenotypes and single nucleotide polymorphisms (SNPs) within neuronal nicotinic acetylcholine receptor genes (nAChRs), the initial physiological targets of nicotine in the central and peripheral nervous system (27–29), and variable-number-of-tandem-repeats (VNTR) polymorphisms located in dopaminergic genes and serotonin transporter genes (30).
