Although nAChRs in CHRNA7, CHRNA9, CHRNA5, CHRNB3, and CHRNA4 were found to be significantly associated with nicotine addiction in early candidate gene studies, GWAS failed to provide support for these findings (31). Instead, independent GWAS have provided evidence for association between common variants within the CHRNA5-CHRNA3-CHRNB4 gene cluster located on chromosome 15 and nicotine dependence (29,32). The studies identified in this review investigated the following SNPs within this cluster: rs16969968 (33,34), rs680244 (34), rs3743078 (33), and rs1051730 (35,36) which is in near-perfect linkage disequilibrium with rs16969968 in Caucasian samples. Numerous studies have demonstrated the association between functional variant rs16969968 and cigarettes per day (CPD) and nicotine dependence (27,29,37), heavy smoking (28,38) and decreased response to nicotine antagonists in vitro (35). The same locus was associated with the risk of lung cancer and chronic obstructive pulmonary disease in several GWAS (22). SNP rs680244 has been associated with variability in CHRNA5 mRNA levels (34). SNP rs3743078 is a proxy for variant rs578776, which has also been associated with nicotine dependence (33). Gene variant rs1051730 has been previously associated with smoking quantity and increased susceptibility for lung cancer and vascular disease among smokers (35).
