“Use of Genetically Informed Methods to Clarify the Nature of the Association Between Cannabis Use and Risk for Schizophrenia”, 2020-11-04 (; similar):
When evaluating efforts to reduce cannabis use as a means of preventing schizophrenia, the proportion of this association that is causal is critical. Given the high heritability of schizophrenia, we reviewed reports that relied on 4 genetic methods (Table) capable of addressing the nature of the cannabis-schizophrenia association. We evaluated 3 hypotheses: (1) it is entirely causal, (2) it is partly causal and partly confounded by genetic/familial effects and/or reverse causation, or (3) it is entirely noncausal. (We are unable to review the literature regarding short-term psychiatric effects of cannabis administration.)
Confounding here refers to genetic risks that increase the probability of both using/misusing cannabis and schizophrenia, thereby explaining at least part of the association. In this example, reverse causality refers to a theoretical underlying mechanism in which schizophrenia liability or symptoms increase the risk of using cannabis. The first 2 methods are natural experiments, discordant relative design, and Mendelian Randomization, that directly evaluate each hypothesis. The 2 other methods, linkage disequilibrium score regression (LDSR) and polygenic risks scores (PRSs), measure genetic associations, which, although less definitive, provide evidence of correlated genetic risks that undermine the plausibility of hypothesis 1.
…As summarized in the Table, when triangulating across 4 genetically informative methods, the findings, with considerable but not complete consistency, argue against hypothesis 1. Although the number of available studies is modest, there is relatively reliable evidence across multiple methods that the cannabis-schizophrenia association stems partly from shared familial/genetic risk factors and/or reverse causation. We also have good evidence against hypothesis 3, ie, familial/genetic risk factors explaining all of the association. The 1 study that directly estimated the degree of familial confounding 4 suggests that it is substantial and accounts for more than half of the observed association. Results from LDSR and PRS methods suggest more modest degrees of confounding while raising the possibility of reverse causation. A prudent conclusion is that the observed cannabis-schizophrenia association in the general population may arise from some potential causal effect of cannabis on the risk of schizophrenia, while an appreciable proportion of the association is not causal. When based on associations observed in the population (ie. without control for confounders), claims made about the changes in risk for schizophrenia stemming from changing levels of cannabis use are very likely to be exaggerated and potentially substantially so.