title: Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample Mendelian randomization study.
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.
  
  
  METHODS
  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.
authors.affiliation: MRC Integrative Epidemiology Unit (IEU), University of Bristol,Bristol,UK.
authors.forename: S H
authors.initials: SH
authors.lastname: Gage
authors.affiliation: MRC Integrative Epidemiology Unit (IEU), University of Bristol,Bristol,UK.
authors.forename: H J
authors.initials: HJ
authors.lastname: Jones
authors.affiliation: Department of Public Health and Primary Care,University of Cambridge, Cambridge,UK.
authors.forename: S
authors.initials: S
authors.lastname: Burgess
authors.affiliation: MRC Integrative Epidemiology Unit (IEU), University of Bristol,Bristol,UK.
authors.forename: J
authors.initials: J
authors.lastname: Bowden
authors.affiliation: MRC Integrative Epidemiology Unit (IEU), University of Bristol,Bristol,UK.
authors.forename: G
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: School of Social and Community Medicine,University of Bristol,Bristol,UK.
authors.forename: S
authors.initials: S
authors.lastname: Zammit
authors.affiliation: MRC Integrative Epidemiology Unit (IEU), University of Bristol,Bristol,UK.
authors.forename: M R
authors.initials: MR
authors.lastname: Munafò
mesh_terms: D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D000074609:Marijuana Use / Q000453:epidemiology*; D057182:Mendelian Randomization Analysis / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D012559:Schizophrenia / Q000453:epidemiology*
keywords: Cannabis; Mendelian randomization; genetics; schizophrenia