The most widely studied genetic variants for tobacco involvement are part of the cluster of genes encoding the alpha 5, alpha 3 and beta 4 subunits (CHRNA5/A3/B4) of the cholinergic nicotinic receptor (42). Specifically, rs16969968, a variant in this gene cluster that causes an amino acid coding change in the gene, has been associated with cigarettes smoked per day at p-values exceeding 10E-70 (β=1.03) (43-45). Each increasing copy of the risk allele contributed to an increase in smoking quantity of 1 cigarette per day. In addition to CHRNA5/A3/B4, genetic variants in CYP2A6, the cytochrome P450 2A6 gene, involved in the oxidation of nicotine and its metabolic product, cotinine, have also been implicated (45). Studies of cannabis involvement have seen less success. The most biologically plausible polymorphisms are in the gene encoding the cannabinoid receptor 1 (CNR1) to which endocannabinoids bind and the gene encoding fatty acid amide hydrolase (FAAH) which encodes the enzyme involved in the metabolism of cannabinoids and lipids (46). However, multiple studies have shown no relationship with these polymorphisms (47).
