The biologic importance of rs16969968 has been shown in several settings. First, the α5 nicotinic receptor is expressed in the brain. Its expression in the striatum and direct interaction with the dopaminergic pathway is particularly relevant to addiction. Second, the protein sequences of CHRNA5 homologs were examined in multiple species (human, chimpanzee, Bolivian squirrel monkey, domestic cow, mouse, chicken, and African clawed frog) and the aspartic acid residue was present in all species.37 This conservation across species suggests that it has functional importance. Third, an in vitro functional study found that α4 α5β2 receptors containing the asparagine amino acid substitution in α5 exhibited decreased response to a nicotine agonist compared with the receptors with the aspartic acid variant in α5.37 This finding suggests that decreased nicotinic receptor function is associated with increased risk for nicotine dependence.
