Although the associations with smoking-related diseases do not represent a fully independent replication of the FTND result, we note that because we often lack detailed information on smoking for subjects with smoking-related diseases there is very little overlap between the group of subjects with FTND data and those with smoking-related diseases. For example, only 140 subjects are both on the early-onset smoking-related disorders list and among the subjects scoring 4 or higher on the heavy smoking index, representing ~8% of the heavy smoking index cases and 4.7% of the subjects with early-onset smoking-related diseases. The overlap between these lists is so small because only a few of the patients with early-onset smoking-related disorders have filled out the FTND questionnaire. Hence, despite the correlation between smoking behavior and the smoking-related diseases our results for FTND and the smoking-related diseases are not due to direct confounding as there is very little overlap between the study groups. Furthermore, as was the case for CHRNA5 (refs 2, 31, 32) the observed effect on FTND and CPD alone is not expected to fully explain the observed OR for smoking-related diseases.
