Part of the shared genetic component has opposite effects on psychotic and cannabis phenotypes, such as genomic regions with negative correlation coefficients and shared loci with discordant effect directions. These results may partly be explained by the fact that both SCZ and BIP are clinically and biologically heterogeneous disorders with a wide range of symptoms, that may exhibit mixed relationships with cannabis phenotypes. For instance, in a sample of SCZ patients, cannabis use was associated with severe positive symptoms but fewer negative symptoms.47 This mixed relationship may also be supported by the results of our enrichment analyses of drug gene-targets. Shared genes for SCZ and cannabis phenotypes showed significant enrichment for genes encoding targets of nicotine and alcohol. Use of nicotine or alcohol is prevalent in cannabis users, and co-users demonstrate a higher rate of psychotic disorder and symptom severity.51 Genes shared between BIP and cannabis phenotypes were enriched for drug targets of duloxetine, an antidepressant52 and reliever of chronic pain.53 Medicinal cannabis use has been linked to both lower self-reported depression54 and pain management.55 Although cannabis use/misuse is also
