A recent series of meta-analyses based on tens of thousands of subjects of European descent confirms the association of chromosome region 15q25.1with smoking heaviness, defined by cigarettes per day (8-11), with the most robust associations being reported for rs16969968 and rs1051730, two highly correlated variants (p<5.57*10−72)(10). In the CHRNA5-A3-B4 region, at least two independent signals have been identified (9, 12). The first signal tagged by rs16969968, a variant that results in an amino acid change in the α5 nicotinic cholinergic receptor (CHRNA5), alters nicotinic receptor conductance in vitro (13, 14). A second, distinct signal tagged by rs680244 is associated with variability in CHRNA5 mRNA levels(15). Resequencing of the CHRNA5-CHRNA3-CHRNB4 locus in subjects of European ancestry identified three common haplotypes in the region spanning CHRNA5 and the 3′ end of CHRNA3 (12), which can be defined by rs16969968 and rs680244 (15).
