Extensive genotyping of the CHRNA5-CHRNA3-CHRNB4 region has provided potential evidence for at least two additional distinct signals for nicotine dependence [4], [7], [8], [20]. A second locus, tagged by rs578776, is associated with nicotine dependence and smoking in several samples of European-ancestry, with the minor allele protective in the sense that it is elevated in controls; rs578776 has only low correlation with rs16969968 in European-ancestry populations (r2 = 0.24 in the HapMap CEU panel), though the linkage disequilibrium (LD) coefficient |D'| is 1. A third important locus in this region is a group of highly correlated SNPs, tagged by rs588765, which are associated with mRNA levels of CHRNA5 in brain tissue [21], [22] and lung tissue [23]–[25] from European-ancestry subjects. When rs16969968 and rs588765 (or correlates) are studied together, three common haplotypes are observed, each with distinct effects on risk [7], [22]. There are hints that other, less common variants (minor allele frequency (MAF)≤5%) also contribute to nicotine dependence in this region, including a fourth locus represented by rs12914008 which has shown a relatively strong odds ratio of 0.73 in European-American subjects [4].
