title: Cannabis use and risk of schizophrenia: a Mendelian randomization study.
abstract: Cannabis use is observationally associated with an increased risk of schizophrenia, but whether the relationship is causal is not known. Using a genetic approach, we took 10 independent genetic variants previously identified to associate with cannabis use in 32 330 individuals to determine the nature of the association between cannabis use and risk of schizophrenia. Genetic variants were employed as instruments to recapitulate a randomized controlled trial involving two groups (cannabis users vs nonusers) to estimate the causal effect of cannabis use on risk of schizophrenia in 34 241 cases and 45 604 controls from predominantly European descent. Genetically-derived estimates were compared with a meta-analysis of observational studies reporting ever use of cannabis and risk of schizophrenia or related disorders. Based on the genetic approach, use of cannabis was associated with increased risk of schizophrenia (odds ratio (OR) of schizophrenia for users vs nonusers of cannabis: 1.37; 95% confidence interval (CI), 1.09-1.67; P-value=0.007). The corresponding estimate from observational analysis was 1.43 (95% CI, 1.19-1.67; P-value for heterogeneity =0.76). The genetic markers did not show evidence of pleiotropic effects and accounting for tobacco exposure did not alter the association (OR of schizophrenia for users vs nonusers of cannabis, adjusted for ever vs never smoker: 1.41; 95% CI, 1.09-1.83). This adds to the substantial evidence base that has previously identified cannabis use to associate with increased risk of schizophrenia, by suggesting that the relationship is causal. Such robust evidence may inform public health messages about cannabis use, especially regarding its potential mental health consequences.
authors.affiliation: Department of Internal Medicine, University Hospital of Lausanne, Lausanne, Switzerland.
authors.forename: J
authors.identifier: 0000-0002-3230-3693
authors.initials: J
authors.lastname: Vaucher
authors.affiliation: Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Keating
authors.affiliation: Centre for Psychiatric Epidemiology and Psychopathology (CEPP), University Hospital of Lausanne, Prilly, Switzerland.
authors.forename: A M
authors.initials: AM
authors.lastname: Lasserre
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital Campus, University of Oxford, Oxford, UK.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: W
authors.initials: W
authors.lastname: Gan
authors.affiliation: Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK.
authors.forename: D M
authors.initials: DM
authors.lastname: Lyall
authors.affiliation: Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK.
authors.forename: J
authors.initials: J
authors.lastname: Ward
authors.affiliation: Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Smith
authors.affiliation: Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK.
authors.forename: J P
authors.initials: JP
authors.lastname: Pell
authors.affiliation: Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow, UK.
authors.forename: N
authors.initials: N
authors.lastname: Sattar
authors.affiliation: Population Health Research Institute, Hamilton Health Sciences, Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada.|Population Genomics Program, Chanchlani Research Centre, McMaster University, Hamilton, ON, Canada.|Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.|Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, ON, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Paré
authors.affiliation: Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.|Medical Research Council Population Health Research Unit at the University of Oxford, Oxford, UK.
authors.forename: M V
authors.initials: MV
authors.lastname: Holmes
mesh_terms: D000328:Adult; D002188:Cannabis / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D002189:Marijuana Abuse / Q000235:genetics / Q000523:psychology; D008385:Marijuana Smoking / Q000009:adverse effects / Q000235:genetics* / Q000523:psychology; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011897:Random Allocation; D012307:Risk Factors; D012559:Schizophrenia / Q000209:etiology* / Q000235:genetics*; D000074285:Smokers / Q000523:psychology; D044465:White People / Q000235:genetics