In the chromosome 15 region, the most biologically credible variant associated with nicotine dependence is rs16969968, a polymorphism that causes an amino acid change from aspartic acid to asparagine (Asp398Asn) in the α5 nicotine receptor subunit. Several lines of evidence point to this variant as having functional importance. The specific region in the α5 protein that includes this polymorphism is highly conserved across different species, which implies biological importance (aspartic acid is conserved in chimpanzee, Bolivian squirrel monkey, domestic cow, mouse, chicken and African clawed frog) (Bierut et al., 2008). An in vitro functional study found that α4α5β2 receptors that only differed by the asparagine amino acid substitution exhibited altered response to a nicotine agonist compared with receptors containing the aspartic acid amino acid (Bierut et al., 2008). Further studies of the nicotinic receptors show that the α5 Asn 398 protein (high risk variant) in the nicotinic acetylcholine receptor lowers Ca2+permeability and increases short-term desensitization in (α4β2)α5, but does not alter the receptor sensitivity to activation (Kuryatov et al., 2011). The high sensitivity to activation and desensitization of (α4β2)α5 nicotine
