Recently, a genome-wide association study of 15 771 Europeans showed that a single nucleotide polymorphism (SNP rs1051730) on chromosome 15q24 was associated with smoking quantity and nicotine dependence [assessed by questionnaire incorporating the Fagerstrom test (9)] among smokers (10). The polymorphism was equally prevalent in smokers and never-smokers, suggesting that it does not predispose to smoking initiation, but to dependence among those who smoke. Each additional copy of the minor, T, allele of the rs1051730 variant was associated with an increase of 0.095 (95% CI 0.075–0.115) smoking quantity units, approximately equal to one cigarette per day (P = 6 × 10−20). The SNP lies within the nicotinic acetylcholine receptor gene, CHRNA3, in a linkage disequilibrium block containing two other strong candidate genes, CHRNA5 and CHRNB4 (10). A recent study showed that the minor allele of the missense polymorphism, D398N, in CHRNA5 (rs16969968), which is highly correlated with rs1051730 (r2 > 0.79), conferred a reduced response to a nicotinic agonist in vitro (P < 0.0001) (11). This polymorphism may therefore be the functional variant responsible for the association with smoking quantity.
