Cannabis use disorder (CanUD) has increased with the legalization of the use of cannabis. Around 20% of individuals using cannabis develop CanUD, and the number of users has grown with increasing ease of access. CanUD and other substance use disorders (SUDs) are associated phenotypically and genetically. We leveraged new CanUD genomics data to undertake genetically-informed analyses with unprecedented power, to investigate the genetic architecture and causal relationships between CanUD and lifetime cannabis use with risk for developing SUDs and substance use traits. Analyses included calculating local and global genetic correlations, genomic structural equation modeling (genomicSEM), and Mendelian Randomization (MR). Results from the genetic correlation and genomicSEM analyses demonstrated that CanUD and cannabis use differ in their relationships with SUDs and substance use traits. We found significant causal effects of CanUD influencing all the analyzed traits: opioid use disorder (OUD) (Inverse variant weighted, IVW β = 0.925 ± 0.082), problematic alcohol use (PAU) (IVW β = 0.443 ± 0.030), drinks per week (DPW) (IVW β = 0.182 ± 0.025), Fagerström Test for Nicotine Dependence (FTND) (IVW β = 0.183 ± 0.052), cigarettes per day (IVW β = 0.150 ± 0.045), current versus former smokers (IVW β = 0.178 ± 0.052), and smoking initiation (IVW β = 0.405 ± 0.042). We also found evidence of bidirectionality showing that OUD, PAU, smoking initiation, smoking cessation, and DPW all increase risk of developing CanUD. For cannabis use, bidirectional relationships were inferred with PAU, smoking initiation, and DPW; cannabis use was also associated with a higher risk of developing OUD (IVW β = 0.785 ± 0.266). GenomicSEM confirmed that CanUD and cannabis use load onto different genetic factors. We conclude that CanUD and cannabis use can increase the risk of developing other SUDs. This has substantial public health implications; the move towards legalization of cannabis use may be expected to increase other kinds of problematic substance use. These harmful outcomes are in addition to the medical harms associated directly with CanUD.

随着大麻使用合法化，大麻使用障碍（CanUD）有所增加。大约 20% 的大麻使用者开发了 CanUD，并且随着使用便利性的提高，用户数量也在增加。 CanUD 和其他物质使用障碍 (SUD) 与表型和遗传相关。我们利用新的 CanUD 基因组学数据以前所未有的能力进行遗传分析，以调查 CanUD 与终生大麻使用与发展 SUD 和物质使用特征风险之间的遗传结构和因果关系。分析包括计算局部和全局遗传相关性、基因组结构方程模型 (genomicSEM) 和孟德尔随机化 (MR)。遗传相关性和基因组扫描电镜分析的结果表明，CanUD 和大麻使用与 SUD 和物质使用特征的关系不同。我们发现 CanUD 影响所有分析特征的显着因果效应：阿片类药物使用障碍 (OUD)（逆变量加权，IVW β  = 0.925 ± 0.082）、有问题的饮酒 (PAU)（IVW β  = 0.443 ± 0.030）、每周饮酒(DPW) (IVW β  = 0.182 ± 0.025)、Fagerström 尼古丁依赖测试 (FTND) (IVW β  = 0.183 ± 0.052)、每天吸烟支数 (IVW β  = 0.150 ± 0.045)、当前吸烟者与以前吸烟者的比较 (IVW β  = 0.178) ± 0.052）和开始吸烟（IVW β  = 0.405 ± 0.042）。我们还发现双向证据表明 OUD、PAU、开始吸烟、戒烟和 DPW 都会增加患 CanUD 的风险。对于大麻使用，推断了与 PAU、吸烟开始和 DPW 的双向关系；使用大麻还与患 OUD 的较高风险相关（IVW β  = 0.785 ± 0.266）。 GenomicSEM 证实 CanUD 和大麻的使用会影响不同的遗传因素。我们的结论是 CanUD 和大麻的使用会增加发展其他 SUD 的风险。这对公共卫生具有重大影响；大麻使用合法化的进程预计会增加其他种类有问题的药物的使用。这些有害后果不包括与 CanUD 直接相关的医疗危害。