Bipolar disorder and cannabis use: a bidirectional two-sample Mendelian randomization study

Aims Cannabis use is associated with a number of psychiatric disorders, however the causal nature of these associations has been difficult to establish. Mendelian randomization (MR) offers a way to infer causality between exposures with known genetic predictors (genome-wide significant single nucleotide polymorphisms (SNPs)) and outcomes of interest. MR has previously been applied to investigate the relationship between lifetime cannabis use (having ever used cannabis) and schizophrenia, depression, and attention-deficit / hyperactivity disorder (ADHD), but not bipolar disorder, representing a gap in the literature. Methods We conducted a two-sample bidirectional MR study on the relationship between bipolar disorder and lifetime cannabis use. Genetic instruments (SNPs) were obtained from the summary statistics of recent large genome-wide association studies (GWAS). We conducted a two-sample bidirectional MR study on the relationship between bipolar disorder and lifetime cannabis use, using inverse-variance weighted regression, weighted median regression and Egger regression. Results Genetic liability to bipolar disorder was significantly associated with an increased risk of lifetime cannabis use: scaled log-odds ratio (standard deviation) = 0.0174 (0.039); P -value = 0.00001. Genetic liability to lifetime cannabis use showed no association with the risk of bipolar disorder: scaled log-odds ratio (standard deviation) = 0.168 (0.180); P -value = 0.351. The sensitivity analyses showed no evidence for pleiotropic effects. Conclusions The present study finds evidence for a causal effect of liability to bipolar disorder on the risk of using cannabis at least once. No evidence was found for a causal effect of liability to cannabis use on the risk of bipolar disorder. These findings add important new knowledge to the understanding of the complex relationship between cannabis use and psychiatric disorders.