Background and Hypothesis The nature of the robust association between cannabis use and schizophrenia remains undetermined. Plausible hypotheses explaining this relationship include the premise that cannabis use causes schizophrenia, increased liability for schizophrenia increases the risk of cannabis use initiation (eg, self-medication), or the bidirectional causal hypothesis where both factors play a role in the development of the other. Alternatively, factors that confound the relationship between schizophrenia and cannabis use may explain their association. Externalizing behaviors are related to both schizophrenia and cannabis use and may influence their relationship. Study Design This study aimed to evaluate whether externalizing behaviors influence the genetic relationship between cannabis use and schizophrenia. We conducted a multivariate genome-wide association analysis of 6 externalizing behaviors in order to construct a genetic latent factor of the externalizing spectrum. Genomic structural equation modeling was used to evaluate the influence of externalizing behaviors on the genetic relationship between cannabis use and schizophrenia. Results We found that externalizing behaviors partially explained the association between cannabis use and schizophrenia by up to 42%. Conclusions This partial explanation of the association by externalizing behaviors suggests that there may be other unidentified confounding factors, alongside a possible direct association between schizophrenia and cannabis use. Future studies should aim to identify further confounding factors to accurately explain the relationship between cannabis use and schizophrenia.

中文翻译：

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对大麻使用和精神分裂症之间遗传关系的影响：外化谱的作用

背景和假设 大麻使用与精神分裂症之间的紧密关联的性质仍未确定。解释这种关系的合理假设包括这样的前提：大麻的使用会导致精神分裂症，精神分裂症的责任增加会增加开始使用大麻的风险（例如自我药疗），或者双向因果假设，其中两个因素在另一个因素的发展中发挥作用。另外，混淆精神分裂症和大麻使用之间关系的因素也可以解释它们之间的关联。外化行为与精神分裂症和大麻使用有关，并可能影响它们之间的关系。研究设计本研究旨在评估外化行为是否影响大麻使用与精神分裂症之间的遗传关系。我们对 6 种外化行为进行了多变量全基因组关联分析，以构建外化谱的遗传潜在因素。基因组结构方程模型用于评估外化行为对大麻使用与精神分裂症之间遗传关系的影响。结果 我们发现，外化行为部分解释了大麻使用与精神分裂症之间的关联，高达 42%。结论 通过外化行为对这种关联的部分解释表明，除了精神分裂症和大麻使用之间可能存在直接关联之外，还可能存在其他未识别的混杂因素。未来的研究应旨在确定进一步的混杂因素，以准确解释大麻使用与精神分裂症之间的关系。