Austin-Zimmerman Isabelle, Thorpe Hayley Ha, Meredith John J, Khokhar Jibran, Ge Tian, Di Forti Marta, Agrawal Arpana, Johnson Emma C, Sanchez-Roige Sandra
Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
medRxiv. 2025 May 21:2025.05.20.25327979. doi: 10.1101/2025.05.20.25327979.
Decades of research have identified a strong association between heavy cannabis use and schizophrenia, with evidence of correlated genetic factors. However, many studies on the genetic relationship between cannabis use and psychosis have lacked data on both phenotypes within the same individuals, creating challenges due to unmeasured confounding. We aimed to address this by using multi-modal data from the All of Us Research Program, which contains genetic data as well as information on schizophrenia diagnosis and cannabis use.
We tested the association between cannabis use disorder () and schizophrenia polygenic scores () and schizophrenia and heavy cannabis use. We tested models where both CUD and schizophrenia PGS were included as joint predictors of heavy cannabis use and schizophrenia case status. We defined three sets of cases based on comorbidities: relaxed (assessing for only the primary condition), strict (excluding for both conditions), and dual-comorbidity (including both conditions).
CUD and schizophrenia polygenic liability were independently associated with heavy cannabis use; the schizophrenia PGS effect was very modest. In contrast, both schizophrenia and CUD PGS were independently associated with schizophrenia, with independent significant effects of CUD PGS. Polygenic liability to CUD was associated with schizophrenia in individuals without a documented history of cannabis use, suggesting widespread pleiotropy.
These findings underscore the need for comprehensive models that integrate genetic risk factors for heavy cannabis use to advance our understanding of schizophrenia aetiology.
数十年的研究已确定大量使用大麻与精神分裂症之间存在密切关联，并有相关遗传因素的证据。然而，许多关于大麻使用与精神病之间遗传关系的研究缺乏同一人群中两种表型的数据，由于存在未测量的混杂因素，带来了挑战。我们旨在通过使用“我们所有人研究计划”的多模态数据来解决这一问题，该计划包含遗传数据以及精神分裂症诊断和大麻使用信息。
我们测试了大麻使用障碍（CUD）与精神分裂症多基因评分（PGS）以及精神分裂症与大量使用大麻之间的关联。我们测试了将CUD和精神分裂症PGS都作为大量使用大麻和精神分裂症病例状态联合预测指标的模型。我们根据合并症定义了三组病例：宽松组（仅评估主要病症）、严格组（排除两种病症）和双重合并症组（包括两种病症）。
CUD和精神分裂症多基因易感性与大量使用大麻独立相关；精神分裂症PGS的影响非常小。相比之下，精神分裂症和CUD PGS都与精神分裂症独立相关，CUD PGS有独立的显著影响。在没有大麻使用记录史的个体中，CUD的多基因易感性与精神分裂症相关，表明存在广泛的多效性。
这些发现强调了需要综合模型来整合大量使用大麻的遗传风险因素，以推进我们对精神分裂症病因学的理解。
