As previously found(3, 4, 15, 16, 54), for CHRNA5-CHRNA3-CHRNB4, the most significantly associated allele was rs1051730[A]. Each copy of rs1051730[A] was associated with a 1.27 increased odds of being a heavy/regular-smoker with a similar effect size in adolescence and mid-adulthood. In line with previous studies(3), frequency of rs1051730[A] was not increased in low-quantity smokers compared to non-smokers(3). This pattern of association suggests that rs1051730 is unlikely to influence smoking initiation, but is more likely to influence smoking severity among subjects who have been already exposed to smoking(3, 17). Indeed, if rs1051730 was associated with increased risk of smoking initiation we would have expected an excess of the A allele also among low quantity-smokers. In addition, most of the CHRNA3-rs1051730[A] effect on smoking behavior in adulthood appears to be direct and not mediated by smoking in adolescence, which is the period of life when smoking initiation occurs in 80–90% of the cases(30, 55). We have also shown that rs1051730[A] is associated with increased risk of smoking persistence. CHRNA3-rs1051730 is located in a region of high linkage disequilibrium. In this regard, genotype
