RT Journal Article SR Electronic T1 Cannabis use and risk of schizophrenia: a Mendelian randomization study JF bioRxiv FD Cold Spring Harbor Laboratory SP 092015 DO 10.1101/092015 A1 Julien Vaucher A1 Brendan J. Keating A1 Aurélie M. Lasserre A1 Wei Gan A1 Donald M. Lyall A1 Joey Ward A1 Daniel J. Smith A1 Jill P. Pell A1 Naveed Sattar A1 Guillaume Paré A1 Michael V. Holmes YR 2016 UL http://biorxiv.org/content/early/2016/12/07/092015.abstract AB Cannabis use is observationally associated with an increased risk of schizophrenia, however whether the relationship is causal is not known. To determine the nature of the association between cannabis use on risk of schizophrenia using Mendelian randomization (MR) analysis, we used ten genetic variants previously identified to associate with cannabis use in 32,330 individuals. Genetic variants were used in a MR analyses of the association of genetically determined cannabis on risk of schizophrenia in 34,241 cases and 45,604 controls from predominantly European descent. Estimates from MR were compared to a metaanalysis of observational studies reporting effect estimates for ever use of cannabis and risk of schizophrenia or related disorders. Genetically determined use of cannabis was associated with increased risk of schizophrenia (OR of schizophrenia for users vs. non-users of cannabis: 1.37; 95%CI, 1.09 to 1.67; P-value=0.007). The corresponding estimate from observational analysis was 1.50 (95% CI, 1.10 to 2.00; P-value for heterogeneity = 0.88). The genetic instrument did not show evidence of pleiotropy on MR-Egger (Egger test, P-value=0.292) nor on multivariable MR accounting for tobacco exposure (OR of schizophrenia for users vs. nonusers of cannabis, adjusted for ever vs. never smoker: 1.41; 95% CI, 1.09-1.83). Furthermore, the causal estimate remained robust to sensitivity analyses. These findings strongly support a causal association between genetically determined use of cannabis and risk of schizophrenia. Such robust evidence may inform public health message about the risks of cannabis use, especially regarding its potential mental health consequences.