The chromosome 15 variant in the α5 nicotinic receptor, rs16969968, which influences the development of nicotine dependence, has also been independently shown to contribute to the occurrence of alcohol and cocaine dependence. The minor allele of rs16969968 that is correlated with an increased risk for nicotine dependence is associated with a decreased risk for alcohol and cocaine dependence (Grucza et al., 2008; Chen et al., 2009; Sherva et al., 2010). This bidirectional association is hypothesized to be due to the involvement of nicotinic receptors with both excitatory and inhibitory modulation of dopamine medicated reward pathways. These data reinforce the importance of variation in the CHRNA5-CHRNA3-CHRNB3 gene cluster for risk of dependence on multiple substances, although the direction of the effects varies across substances. In addition, variants in this region influence the initial responses to alcohol and nicotine in adolescents (Schlaepfer et al., 2008).
