Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample Mendelian randomization study

Background: Observational associations between cannabis and schizophrenia are well documented, but ascertaining causation is more challenging. We used Mendelian randomization (MR), utilizing publicly available data as a method for ascertaining causation from observational data. Methods: We performed bi-directional two-sample MR using summary level genomewide data from the International Cannabis Consortium (ICC) and the Psychiatric Genomics Consortium (PGC2). Single nucleotide polymorphisms (SNPs) associated with cannabis initiation (P < 10-5) and schizophrenia (P < 5x10-8) were combined using an inverse-variance weight fixed-effects approach. We also used height and education genomewide-association study data, representing negative and positive control analyses. Results: There was some evidence consistent with a causal effect of cannabis initiation on risk of schizophrenia (OR 1.04 per doubling odds of cannabis initiation, 95% CI 1.01, 1.07, P = 0.019). There was strong evidence consistent with a causal effect of schizophrenia risk on likelihood of cannabis initiation (OR 1.10 per doubling of the odds of schizophrenia, 95% CI 1.05, 1.14, P = 2.64 × 10-5). Findings were as predicted for the negative control (height OR 1.00, 95% CI 0.99 to 1.01, P = 0.90) but weaker than predicted for the positive control (years in education OR 0.99, 95% CI 0.97 to 1.00, P = 0.066) analyses. Conclusions: Our results provide some that cannabis initiation increases the risk of schizophrenia, though the size of the causal estimate is small. We find stronger evidence that schizophrenia risk predicts cannabis initiation, possibly as genetic instruments for schizophrenia are stronger than for cannabis initiation.