Third, further phenotypic refinement is possible. We did not consider substance abuse criteria, nor did we use the newer diagnostic system, DSM-5 (American Psychiatric Association 2013). Our threshold for exposure was a single use for all substances except nicotine; therefore, the genetic effect of rs1799971 detected by our analyses may involve a combination of effects on development of regular/repeated use and effects on dependence. We focused on dichotomous diagnoses for each substance. For nicotine, we examined heavy/light smoking as the most widely available nicotine trait in our datasets. Consistency of results was confirmed using DSM-IV and Fagerström Test of Nicotine Dependence criteria when available. Because we focused on dichotomous diagnoses that could then be combined into the general substance dependence diagnosis, we did not examine quantitative or categorical cigarettes-per-day.
