These findings are consistent with a common underlying shared genetic liability to schizophrenia or substance use disorder. Other possible models for the observed association include mediation by schizophrenia and mediation by substance use disorder (Figure 1). The mediation by schizophrenia model is commonly referred to as a “self-medication” model of comorbidity, where the development of schizophrenia subsequently leads to the onset of substance use disorder under the hypothesis that individuals use and misuse a substance to reduce symptomatology. In this study, because the self-reported prevalence of psychotic symptoms in these data is less than 5%, the observed association between the polygenic risk score for schizophrenia and the substance use disorder phenotypes cannot be explained through mediation by schizophrenia. However, biological risk of schizophrenia may be expressed in ways other than psychotic symptoms, and mediation through subthreshold symptoms of schizophrenia could drive the association seen with substance use disorder. The next mechanism, the development of schizophrenia mediated by substance use disorder, cannot be directly tested in these datasets. In addition, because the majority of the schizophrenia datasets do not have substance
