Cannabis abuse and age at onset in schizophrenia patients with large, rare copy number variants

Background: Large deletions are found to a greater extent in patients with schizophrenia compared with healthy controls. This study aims to investigate clinical symptomatology and substance abuse rates in patients with large (>. 500. kb), rare (<. 1 of cohort) deletions and duplications compared with schizophrenia patients in general. Methods: 633 schizophrenia patients, including 60 with large (>. 500. kb), rare (<. 1 of cohort) deletions and 74 with large, rare duplications, who formed part of a large genome-wide association study, were assessed for alcohol and cannabis abuse rates as well as a range of symptom measures using the Diagnostic Interview for Genetic Studies (DIGS), Family Interview for Genetic Studies (FIGS), and medical records. Results: Patients with large, rare deletions had significantly less cannabis abuse rates but comparable alcohol abuse rates, with an age at onset later than those without large, rare deletions. There was no significant difference in any substance abuse or clinical symptom rates between patients with and without large, rare duplications, but an interaction did exist between cannabis abuse, duplication status, and age at onset, with cannabis abuse resulting in an earlier age at onset only in those without a large, rare duplication. Similarly, patients with a large, rare duplication had a later onset age for cannabis abuse/dependence. Conclusions: Schizophrenia patients with large, rare deletions were less likely to have comorbid cannabis abuse over their lifetime. This provides support for a threshold model of risk with those carrying a schizophrenia-associated copy number variation less reliant on environmental insults. Patients with large, rare duplications were protected against earlier onset of schizophrenia in the presence of comorbid cannabis abuse in addition to later onset of cannabis abuse itself.