The observed genetic correlation between smoking behaviors and schizophrenia suggests that shared genetic variation contributes to the comorbidity between schizophrenia and smoking behaviors. Shared genetic variation could contribute either directly to the disorders (pleiotropy), or may be mediated (for example, genetic variation contributes to nicotine dependence, which then contributes to schizophrenia). As discussed in the introduction, there is a growing amount of evidence that nicotine dependence contributes to schizophrenia (Gage et al., 2014; Kendler et al., 2015). However, LD score regression cannot distinguish the difference between pleiotropy or mediation (or, most likely, a combination of pleiotropy and mediation). Therefore, future studies are necessary to dissect the mechanism of association. For example, pleiotropy can be explored for a genetic locus associated with both nicotine dependence and schizophrenia by stratifying the schizophrenia sample into never smokers and ever smokers (Wium-Andersen et al., 2015).
