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

  • S. H. Gage (a1) (a2), H. J. Jones (a1) (a3), S. Burgess (a4), J. Bowden (a1) (a3) (a5), G. Davey Smith (a1) (a3), S. Zammit (a3) (a6) and M. R. Munafò (a1) (a2)...
Background</title> <p>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.</p> </sec> <sec secType='methods' id='sec_a2'> <title>Method</title> <p>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 (<span class='italic'>p</span> < 10<span class='sup'>−5</span>) and schizophrenia (<span class='italic'>p</span> < 5 × 10<span class='sup'>−8</span>) 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.</p> </sec> <sec secType='results' id='sec_a3'> <title>Results</title> <p>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, <span class='italic'>p</span> = 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, <span class='italic'>p</span> = 2.64 × 10<span class='sup'>−5</span>). Findings were as predicted for the negative control (height: OR 1.00, 95% CI 0.99–1.01, <span class='italic'>p</span> = 0.90) but weaker than predicted for the positive control (years in education: OR 0.99, 95% CI 0.97–1.00, <span class='italic'>p</span> = 0.066) analyses.</p> </sec> <sec secType='conclusion' id='sec_a4'> <title>Conclusions
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 < 10−5) and schizophrenia (p < 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.

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This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Corresponding author
*Address for correspondence: S. H. Gage, Ph.D., School of Experimental Psychology, University of Bristol, 12a Priory Road, Bristol BS8 1TU, UK. (Email: suzi.gage@bristol.ac.uk)
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