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

TLDR

Observational studies link cannabis use to schizophrenia, but establishing causation remains difficult. This study applies Mendelian randomization to test whether cannabis use causally affects schizophrenia risk. Using bi‑directional two‑sample MR with genome‑wide summary data from the International Cannabis Consortium and the Psychiatric Genomics Consortium, the authors combined cannabis‑associated SNPs (p<10⁻⁵) and schizophrenia‑associated SNPs (p<5×10⁻⁸) via inverse‑variance‑weighted fixed‑effects, and performed negative and positive control analyses with height and education GWAS data. The analysis shows a modest causal effect of cannabis initiation on schizophrenia risk (OR 1.04, 95 % CI 1.01–1.07, p = 0.019) and stronger evidence that schizophrenia risk increases cannabis initiation (OR 1.10, 95 % CI 1.05–1.14, p = 2.64×10⁻⁵), with controls behaving as expected.

Abstract

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. Method We performed bi-directional two-sample MR using summary-level genome-wide data from the International Cannabis Consortium (ICC) and the Psychiatric Genomics Consortium (PGC2). Single nucleotide polymorphisms (SNPs) associated with cannabis initiation ( p &lt; 10 −5 ) and schizophrenia ( p &lt; 5 × 10 −8 ) were combined using an inverse-variance-weighted fixed-effects approach. We also used height and education genome-wide 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 [odds ratio (OR) 1.04 per doubling odds of cannabis initiation, 95% confidence interval (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 0.99–1.01, p = 0.90) but weaker than predicted for the positive control (years in education: OR 0.99, 95% CI 0.97–1.00, p = 0.066) analyses. Conclusions Our results provide some that cannabis initiation increases the risk of schizophrenia, although 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.