A recent study of rare variants in CHRNA4 based on a comparison of sequence data for exon 5 for 1209 cases and 1183 controls observed that rare non-synonymous variants were underrepresented in nicotine-dependent subjects, and the authors concluded that such variants might be protective against ND.33 In the case of R336C, our results clearly show the opposite, namely that the variant encoding this mutation confers risk of ND and its consequences on health, and comparison of the results for the various variants such as P451L and R336C reveals a range of effect sizes (Table 1), suggesting that treating all rare missense variants in CHRNA4 alike is not a good approach. We note that only one carrier of R336C was observed by Xie et al.,33 a case with ND.
