In the chromosome 15 region, the second independent genetic association with nicotine dependence is marked by rs880395 (Saccone et al., 2010a), and functional studies suggest a distinct biological mechanism: altered α5 nicotinic receptor mRNA expression (Wang et al., 2009; Falvella et al., 2010; Smith et al., 2011). Variants tagged by rs880395, which are more than 10kb upstream of CHRNA5, result in a 2.5 to 4 fold difference in α5 nicotinic receptor mRNA expression in the brain. High expression of CHRNA5 mRNA is correlated with an increased risk of heavy smoking and nicotine dependence (Wang et al., 2009). This change in expression is not seen in lymphocytes, which demonstrates that genetic variants can have tissue specific biologic effects (Smith et al., 2011).
