While epidemiologic studies support a role for heavy, high-potency cannabis use on first episode psychosis, genetic models of causation suggest reverse causal effects of schizophrenia on cannabis use liability. We estimated the genetic relationship between cannabis use disorder (CUD) and schizophrenia (SCZ) and tested whether liability for CUD is causally associated with increased liability to SCZ while adjusting for tobacco smoking.
This study used summary statistics from published genome-wide association studies (GWAS). We used genomic structural equation modeling, latent causal variable analysis, and multivariable Mendelian Randomization to examine genetic relationships between CUD, cannabis ever-use, ever-smoked regularly, nicotine dependence, and SCZ, and to test for a causal relationship between liability to CUD and liability to SCZ.
GWAS were published previously as part of international consortia.
Sample sizes of the GWAS summary statistics used in this study ranged from 161,405 to 357,806 individuals of European ancestry.
Genome-wide summary statistics for genetic associations with CUD and SCZ were the primary measurements, while summary statistics for cannabis ever-use, ever-smoked regularly, and nicotine dependence were included as additional variables in the genomic structural equation models and the multivariable Mendelian Randomization analyses.
Genetic liability to CUD was significantly associated with SCZ (beta = 0.29, 95% CI = [0.11, 0.46], p = 0.001), even when accounting for cannabis ever-use, ever-smoked tobacco regularly, and nicotine dependence as simultaneous predictors. We found mixed evidence of a causal relationship, with the latent causal variable analysis finding no evidence of causality (genetic causality proportion = -0.08, 95% CI = [-0.40, 0.23], p = 0.87) but the multivariable Mendelian Randomization analyses suggesting a significant, risk-increasing effect of CUD on liability to SCZ (beta = 0.10, 95% CI = [0.02, 0.18], p = 0.02), accounting for the additional risk factors (cannabis ever-use, ever-smoked tobacco regularly, and nicotine dependence).
Genetic liability for cannabis use disorder appears to be robustly associated with schizophrenia, above and beyond tobacco smoking and cannabis ever-use, with mixed evidence to support a causal relationship between cannabis use disorder and schizophrenia.

This article is protected by copyright. All rights reserved.