There are at least two distinct biological mechanisms in the nAChR gene cluster on chromosome 15 that alter the risk for developing nicotine dependence. One mechanism involves the variant rs16969968 (D398N), which likely alters protein structure and receptor function. An in vitro functional analysis demonstrated that the maximal response to agonist per receptor was twofold higher for the α4β2α5D398 nAChR variant relative to the α4β2α5N398 nAChR variant (17). The second potential mechanism is altered mRNA expression of CHRNA5 (139a)(139). Several variants located upstream of the coding region and intronic regions of CHRNA5 (i.e., rs588765) are strongly associated with the variability in CHRNA5 mRNA expression observed in the human frontal cortex. Subjects homozygous for the minor allele of rs588765 showed a 2.9-fold increase in CHRNA5 mRNA expression compared with subjects homozygous for the major allele (139a)(139). The rs588765 polymorphism and highly correlated variants are only weakly correlated with the D398N variant. The N398 variant, which greatly increases risk for nicotine dependence, occurs primarily on the background of low mRNA expression of CHRNA5. The nonrisk variant D398 occurs on both high- and
