Despite these limitations, this study has implications for etiological research and public health. With respect to etiology, our study makes 3 contributions: First, next generation sequencing studies and other efforts to ascertain causal variants responsible for GWAS signals may maximize their discovery potential by focusing on samples of young people strategically selected to reflect important developmental transitions. Such work could use experimental designs to test hypotheses about mechanisms of genetic risk on post-initiation phenotypes. Second, we demonstrated that a genetic risk score based on the assumption of additive risks can be used to follow-up GWAS results in a birth cohort far smaller than the original discovery samples. Future etiological research can use genetic risk scores to apply GWAS results to longitudinal studies. Third, results are consistent with the hypothesis in pediatric medicine that some adolescents, after only experimental use, are prone to quickly become heavy users and dependent.62 This finding suggests gene-environment interaction (GxE) analyses of smoking and nicotine dependence may profit from a focus on environments that coincide with or immediately precede the adolescent period and influence the propensity
