Once genetic factors contributing to disease susceptibility have been identified, the next goal is to find factors that can reduce an individual’s genetic risk. We designed this large meta-analysis to determine whether age at onset modifies a known genetic association with smoking behavior. We found that the genetic risk of heavy smoking (as measured by the rs16969968 A allele) is greater in early-onset smokers (onset of smoking at ≤16 years) compared with later-onset smokers. These results are consistent with the findings of Weiss and colleagues10,28 and are supported by animal models in which the developing adolescent brain has been shown to be particularly vulnerable to addictive effects of nicotine31–35 and by human studies suggesting that adolescent neurodevelopment is a particularly vulnerable period for the development of addiction.36 In addition, the increased association in early-onset smokers is consistent with the epidemiologic observation of increased vulnerability to dependence in early-onset smokers.9,24,26 With this large international collaborative analysis, we also demonstrated that the stronger association of rs16969968 in white early-onset smokers is consistent across different continents (North America, Europe, and Australia).
