In-depth analyses of the region led to the discovery of additional SNPs that form a haplotype with rs16969968 to modify the expression of CHRNA5.32,36,38 The SNP rs588765 was found to be associated with nicotine dependence and to modify expression of CHRNA5. In addition, together with rs16969968, it forms a haplotype to alter the risk of nicotine dependence. Although rs588765 can lead to high expression and low expression of CHRNA5, and rs16969968 can lead to high risk and low risk for nicotine dependence, only 3 haplotypes exist in the population (Table 1): high risk (rs16969968) and low expression (rs588765), low risk (rs16969968) and low expression (rs588765), and low risk (rs16969968) and high expression (rs588765). The lowest risk of nicotine dependence occurs with the low-expression allele of rs588765 and the low-risk allele of rs16969968, and the highest risk for nicotine dependence occurs with the low-expression allele of rs588765 and the high-risk allele of rs16969968. A similar association was seen in a population of African Americans with the SNP rs555018, an SNP in high LD with rs588765 in European Americans and African Americans, suggesting that rs555018 is associated with variable expression of CHRNA5.32
