Using genetic information to inform policy on cannabis
Authors: Lindsey A Hines, Jorien L Treur, Hannah J Jones, Hannah M Sallis, Marcus R Munafò
Journal: The Lancet Psychiatry (2020)

Cannabis is a commonly used drug, and a substantial minority of individuals who use it frequently will develop cannabis use disorder (CUD). Johnson and colleagues1Johnson EC Demontis D Thorgeirsson TE et al.A large-scale genome-wide association study meta-analysis of cannabis use disorder.Lancet Psychiatry. 2020; (published online Oct 20.)https://doi.org/10.1016/S2215-0366(20)30339-4Google Scholar identify a high genetic correlation between liability to frequent cannabis use and CUD. This finding is in line with previous twin research, which has identified a high correlation between additive genetic influences acting on exposure to cannabis, frequency of cannabis use, and CUD.2Hines LA Morley KI Rijsdijk F et al.Overlap of heritable influences between cannabis use disorder, frequency of use and opportunity to use cannabis: trivariate twin modelling and implications for genetic design.Psychol Med. 2018; 48: 2786-2793Google Scholar One straightforward interpretation is that frequent use is on the causal pathway to CUD; however, Johnson and colleagues1Johnson EC Demontis D Thorgeirsson TE et al.A large-scale genome-wide association study meta-analysis of cannabis use disorder.Lancet Psychiatry. 2020; (published online Oct 20.)https://doi.org/10.1016/S2215-0366(20)30339-4Google Scholar do not explore this formally (eg, by using Mendelian randomisation, which uses genetic variants as proxies for exposures of interest). In the present study and the previous twin study, a moderate proportion of genetic influences acting on liability to CUD appear to be unique from those acting on liability to frequency of use. These findings emphasise the importance of considering the stage-sequential nature of drug use. CUD cannot occur without exposure to cannabis and is preceded by escalation from initiation to frequent use. Research from the USA suggests that an increase in CUD follows legalisation of recreational cannabis use.3Cerda M Mauro C Hamilton A et al.Association between recreational marijuana legalization in the United States and changes in marijuana use and cannabis use disorder from 2008 to 2016.JAMA Psychiatry. 2019; 77: 165-171Google Scholar It is plausible that this rise in CUD is not simply a consequence of increased availability, but that the subsequent increases in population-level cannabis use allow the expression of genetic liability to CUD in individuals who were previously unexposed. This possibility has important implications for public health in relation to cannabis legalisation, as the perceived benefits of policy liberalisation should be balanced against the health risks that might be experienced by a notable minority of individuals using cannabis. CUD is characterised by negative health and social effects, but Johnson and colleagues1Johnson EC Demontis D Thorgeirsson TE et al.A large-scale genome-wide association study meta-analysis of cannabis use disorder.Lancet Psychiatry. 2020; (published online Oct 20.)https://doi.org/10.1016/S2215-0366(20)30339-4Google Scholar show that polygenic risk for CUD is also associated with psychiatric phenotypes. A key question is whether reducing cannabis use is likely to improve mental health. The identification of genetic markers for CUD can provide insights into the causal pathways between CUD and psychiatric outcomes. Although Johnson and colleagues explore some causal pathways,1Johnson EC Demontis D Thorgeirsson TE et al.A large-scale genome-wide association study meta-analysis of cannabis use disorder.Lancet Psychiatry. 2020; (published online Oct 20.)https://doi.org/10.1016/S2215-0366(20)30339-4Google Scholar they do not examine CUD and schizophrenia. Given ongoing debate about the causal nature of this relationship, future work on this area is warranted. Mendelian randomisation has previously been applied to lifetime cannabis use and schizophrenia.4Pasman JA Verweij KJH Gerring Z et al.GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia.Nat Neurosci. 2018; 21: 1161-1170Google Scholar Although lifetime use is not an ideal measure, as it includes those who might have used cannabis only a few times, there was stronger evidence that liability to cannabis use increased the risk of schizophrenia. It would be interesting to extend this work by looking at schizophrenia in relation to CUD and cannabis use frequency (once such genome-wide association studies become available). Although Johnson and colleagues1Johnson EC Demontis D Thorgeirsson TE et al.A large-scale genome-wide association study meta-analysis of cannabis use disorder.Lancet Psychiatry. 2020; (published online Oct 20.)https://doi.org/10.1016/S2215-0366(20)30339-4Google Scholar used Latent Causal Variable analysis to account for sample overlap, this method does not allow simultaneous bidirectional effects.5O'Connor LJ Price AL Distinguishing genetic correlation from causation across 52 diseases and complex traits.Nat Genet. 2018; 50: 1728-1734Google Scholar For future work, formal methods of Mendelian randomisation would be more informative, combined with a method like genomic structural equation modelling to model directional relationships, which is not biased by sample overlap.6Grotzinger AD Rhemtulla M de Vlaming R et al.Genomic structural equation modelling provides insights into the multivariate genetic architecture of complex traits.Nat Hum Behav. 2019; 3: 513-525Google Scholar Given the high correlation between cannabis use and tobacco use, and the fact that one of the top genetic variants associated with CUD is located near a nicotinic acetylcholine receptor gene, studies on the association between cannabis use and misuse and psychiatric outcomes should also account for tobacco use. This inclusion is particularly important given evidence for a causal role for tobacco use in psychiatric outcomes.7Jones HJ Gage SH Heron J et al.Association of combined patterns of tobacco and cannabis use in adolescence with psychotic experiences.JAMA Psychiatry. 2018; 75: 240-246Google Scholar, 8Wootton RE Richmond RC Stuijfzand BG et al.Evidence for causal effects of lifetime smoking on risk for depression and schizophrenia: a mendelian randomisation study.Psychol Med. 2019; (published online Nov 6.)https://doi.org/10.1017/S0033291719002678Google Scholar Methods, such as multivariable Mendelian randomisation, would allow the unique causal effects of tobacco and cannabis use on these outcomes to be better understood.9Sanderson E Davey Smith G Windmeijer F Bowden J An examination of multivariable mendelian randomization in the single-sample and two-sample summary data settings.Int J Epidemiol. 2019; 48: 713-727Google Scholar The correlation between cannabis use and tobacco use also highlights the potential for pleiotropic effects of genetic variants on these (and other) outcomes. It will be important to understand the underlying traits that these variants capture (which might not necessarily be the measured trait) as they begin to be used in causal analyses. Mendelian randomisation is increasingly being used to investigate causal pathways between modifiable exposures and a range of outcomes. The work of Johnson and colleagues1Johnson EC Demontis D Thorgeirsson TE et al.A large-scale genome-wide association study meta-analysis of cannabis use disorder.Lancet Psychiatry. 2020; (published online Oct 20.)https://doi.org/10.1016/S2215-0366(20)30339-4Google Scholar provides further opportunities to understand the harms of cannabis use. In particular, there is now increasing scope to explore the complex pathways between stages of substance use (eg, from initiation to frequency of use and dependence), and the use of multiple substances (eg, the common use of cannabis and tobacco, which makes their epidemiological dissection challenging). To support strong causal inference, and therefore robust public health policies, findings from Mendelian randomisation should be considered alongside those from other methodological approaches that also aim to understand the harms of cannabis use. This approach is known as triangulation.10Munafo MR Davey Smith G Robust research needs many lines of evidence.Nature. 2018; 553: 399-401Google Scholar Understanding these pathways will be crucial if evidence-based public health policies are to be implemented. All authors report contributing to the International Cannabis Consortium. LAH and JLT contributed equally to the writing of this Comment. A large-scale genome-wide association study meta-analysis of cannabis use disorderThese findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder. Full-Text PDF Open Access