Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
Addiction. 2021 Nov;116(11):3227-3234. doi: 10.1111/add.15534. Epub 2021 May 19.
While epidemiological studies support a role for heavy, high-potency cannabis use on first-episode psychosis, genetic models of causation suggest reverse causal effects of schizophrenia on cannabis use liability. We estimated the genetic relationship between cannabis use disorder (CUD) and schizophrenia (SCZ) and tested whether liability for CUD is causally associated with increased liability to SCZ while adjusting for tobacco smoking.
This study used summary statistics from published genome-wide association studies (GWAS). We used genomic structural equation modeling, latent causal variable analysis, and multivariable Mendelian randomization to examine genetic relationships between CUD, cannabis ever-use, ever-smoked tobacco regularly, nicotine dependence and SCZ, and to test for a causal relationship between liability to CUD and liability to SCZ.
Genome-wide association studies were published previously as part of international consortia.
Sample sizes of the GWAS summary statistics used in this study ranged from 161 405 to 357 806 individuals of European ancestry.
Genome-wide summary statistics for CUD and SCZ were the primary measurements, while summary statistics for cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence were included as additional variables in the genomic structural equation models and the multivariable Mendelian randomization analyses.
Genetic liability to CUD was significantly associated with SCZ [β = 0.29, 95% confidence interval (CI) = 0.11, 0.46, P = 0.001], even when accounting for cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence as simultaneous predictors. We found mixed evidence of a causal relationship, with the latent causal variable analysis finding no evidence of causality (genetic causality proportion = -0.08, 95% CI = -0.40, 0.23, P = 0.87) but the multivariable Mendelian randomization analyses suggesting a significant, risk-increasing effect of CUD on liability to SCZ (β = 0.10, 95% CI = 0.02, 0.18, P = 0.02), accounting for the additional risk factors (cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence).
Genetic liability for cannabis use disorder appears to be robustly associated with schizophrenia, above and beyond tobacco smoking and cannabis ever-use, with mixed evidence to support a causal relationship between cannabis use disorder and schizophrenia.
尽管流行病学研究支持重度、高效力大麻使用与首发精神病有关，但遗传因果模型表明精神分裂症对大麻使用倾向有反向因果效应。我们估计了大麻使用障碍（CUD）与精神分裂症（SCZ）之间的遗传关系，并在调整吸烟因素的情况下，检验了 CUD 易感性是否与 SCZ 易感性的增加有关。
本研究使用了已发表的全基因组关联研究（GWAS）的汇总统计数据。我们使用基因组结构方程模型、潜在因果变量分析和多变量孟德尔随机化来研究 CUD、大麻使用史、定期吸食烟草、尼古丁依赖与 SCZ 之间的遗传关系，并检验 CUD 易感性与 SCZ 易感性之间是否存在因果关系。
GWAS 汇总统计数据以前是作为国际联盟的一部分发表的。
本研究使用的 GWAS 汇总统计数据的样本量范围为 161405 至 357806 名欧洲血统个体。
CUD 和 SCZ 的全基因组汇总统计数据是主要的测量指标，而大麻使用史、定期吸食烟草和尼古丁依赖的汇总统计数据则作为同时预测因子包含在基因组结构方程模型和多变量孟德尔随机化分析中。
CUD 的遗传易感性与 SCZ 显著相关[β=0.29，95%置信区间（CI）=0.11，0.46，P=0.001]，即使同时考虑大麻使用史、定期吸食烟草和尼古丁依赖作为预测因子也是如此。我们发现因果关系的证据存在混合，潜在因果变量分析未发现因果关系（遗传因果比例=-0.08，95%CI=-0.40，0.23，P=0.87），但多变量孟德尔随机化分析表明 CUD 对 SCZ 易感性有显著的、风险增加的影响（β=0.10，95%CI=0.02，0.18，P=0.02），同时考虑了其他风险因素（大麻使用史、定期吸食烟草和尼古丁依赖）。
大麻使用障碍的遗传易感性似乎与精神分裂症显著相关，超出了吸烟和大麻使用史的影响，因果关系的证据存在混合，支持大麻使用障碍与精神分裂症之间存在因果关系。
