We have presented several lines of evidence for the role of a variant encoding R336C in smoking behavior and risk of smoking-related diseases. The variant is rare, but there appears to be a founder effect in Iceland, allowing us to perform association studies with adequate power. First, there is independent and genome-wide significant association between common markers and FTND in the region.4 Second, testing a small number of missense variants in CHRNA4, we find significant association of the R336C variant with FTND and other smoking behavior phenotypes. Third, guided by previous results for CHRNA5 and smoking-related diseases,12 we find significant association with four smoking-related diseases, and highly significant association with the early-onset forms. Fourth, functional data show that the R336C substitution influences function, shifting the equilibrium following nicotine exposure in favor of a lower-sensitivity form.18 When taken together, these results allow us to conclude that carriers of this variant have increased risk of nicotine addiction and heavy smoking, which in turn confers considerable risk and lowered age of onset for a number of serious smoking-related diseases through gene–environment correlations34 akin to those previously observed for the D398N mutation in CHRNA5.2, 12
