Recently, strong genetic associations with nicotine dependence have been found in the nicotinic receptor subunit CHRNA5. It seems that there are at least 2 distinct biologic mechanisms that alter the risk of nicotine dependence. The first biologic mechanism is caused by an amino acid change in CHRNA5, in the nonsynonymous SNP rs16969968. Functional studies have found that expression of the minor variant leads to reduced response to a nicotinic agonist. The second mechanism altering risk of nicotine dependence is through altered expression of the α5 mRNA. A second group of SNPs in the region, including rs588765 and rs555018, is associated with variable expression of CHRNA5. The combination of altered protein and variable mRNA expression leads to different levels of addiction risk.
