Analysis suggested no evidence for a causal association of lifetime cannabis use and cannabis use disorder with primary open-angle glaucoma
European investigators, led by first author Andreas Katsimpris, MD, did not identify an association of genetic liability to lifetime cannabis use and cannabis use disorder with primary open-angle glaucoma (POAG), the most common type of glaucoma.1 Dr Katsimpris is from the Princess Alexandra Eye Pavilion, Edinburgh, Scotland.
The association between cannabis use and intraocular pressure (IOP) has been studied before, but the association with POAG is not clear, the investigators pointed out.
The use of cannabis was suggested to protect against POAG by a salutary effect on IOP,2 without knowing the exact pathogenetic mechanism of this phenomenon. IOP decreases were hypothesised to result from activation of the cannabinoid-related receptors in the ciliary body by Δ9-tetrahydrocannabinol, the psychoactive constituent of cannabis,3 with resultant decreased aqueous humor production by the ciliary body and IOP decreases. Another theory forwarded the notion that the IOP-lowering effect of cannabis is mediated through a decrease in blood pressure.4 However, this mechanism might increase the risk of POAG because it lowers ocular perfusion pressure, thus compromising optic nerve head perfusion.5
Dr Katsimpris and colleagues explained that the rationale for the study under discussion, considering the high incidence of glaucoma and the limitations of the current antiglaucoma agents, was the focus on identifying novel treatments that would work against glaucoma, which includes cannabis. They noted that although cannabinoids exert a lowering effect on IOP when administered intravenously, orally, or by smoking,2 no long-term and adequately sized clinical trials have tested cannabinoid treatment in POAG.
To determine the association, the investigators explained that they used human genetic data to assess through Mendelian randomisation (MR) if cannabis use affects POAG. MR, according to the authors, is a form of instrumental variable analysis that uses genetic variants as instruments.6
The study was a two-sample, summary-based MR and used summary statistics from 3 large genome-wide association studies (GWAS) of lifetime cannabis use,7 cannabis use disorder8 and POAG.9 The investigators calculated the causal association between cannabis use and cannabis use disorder with POAG by combining these estimates. The investigators used 5 single-nucleotide polymorphism (SNP) data obtained from 184,765 individuals of European descent who used cannabis over their lifetime in the International Cannabis Genome Research Consortium, 23andMe and UK Biobank.7
Eleven SNPs associated with cannabis use disorder were obtained from a GWAS meta-analysis of 17,068 cases and 357,219 controls of European descent, derived from the Psychiatric Genomics Consortium Substance Use Disorders working group, Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) and deCODE.8 Finally, SNP-POAG associations were taken from a GWAS meta-analysis of 16,677 POAG cases and 199,580 controls of European ancestry9 from 16 participating studies, they explained.
Data analysis showed “no evidence for a causal association of lifetime cannabis use and cannabis use disorder with POAG (odds ratio of outcome per doubling of the odds of exposure [95% confidence interval]: 1.04 [0.88; 1.23] for lifetime cannabis use and 0.97 [0.92; 1.03] for cannabis use disorder).”
The investigators found that the 5 selected SNPs explained 0.09% of the variance in the lifetime cannabis use and the F-statistics for all SNPs were 30.7 or greater. The 11 selected SNPs for cannabis use disorder explained 0.08% of the phenotypic variance and had an F-statistic of 25.5 or greater.
The investigators found that the MR analysis suggested no evidence for a causal association of lifetime cannabis use and cannabis use disorder with POAG (odds ratio [OR] of outcome/doubling of the odds of exposure [95% confidence interval]: 1.04 [0.88; 1.23] for lifetime cannabis use and 0.97 [0.92; 1.03] for cannabis use disorder).
“We concluded that our data provided evidence for a lack of association of genetic liability to lifetime cannabis use and cannabis use disorder with POAG. Triangulation of evidence from different types of research studies, with different key sources of bias, is warranted to confirm these results,” Dr Katsimpris and colleagues commented.