PRS for cannabis use disorder were computed using PRS-CS40 for each of the 66 915 genotyped individuals of European descent in BioVU (appendix pp 16–17). Genotyping and quality control of this sample have been described elsewhere.41 A logistic regression model was fitted to each of 1335 case or control phenotypes that had at least 100 cases to estimate the odds of each diagnosis given the PRS for cannabis use disorder, after adjustment for sex, median age of the longitudinal electronic health record measurements, and the top ten ancestral principal controls. To explore whether pleiotropic effects of the PRS for cannabis use disorder were mediated by smoking behaviours, we did two phenotype-wide association study (PheWAS) sensitivity analyses: a PheWAS on summary statistics of cannabis use disorder that had been conditioned on the top smoking initiation loci using mtCOJO,35 and a PheWAS using a diagnosis of tobacco use disorders as an additional covariate in the regression model, which is a conservative over-correction given the extremely high comorbidity expected between cannabis use disorder and tobacco use disorder. We used a Bonferroni-corrected phenome-wide significance
