Genetic Basis of the Risk and Consequences of Cannabis Exposure in Humans

人类大麻使用障碍和大麻素反应的遗传学 大麻在世界各地被广泛使用，并与包括大麻使用障碍在内的负面后果有关 (CanUD)、精神病和认知障碍等。鉴于“娱乐”的合法化和 全球“医用”大麻，大麻供应的增加，大麻的效力更高， 高效力大麻素产品的可获得性、大麻的商业化以及大麻使用率的上升 对于大麻的使用，了解遗传因素如何影响个人的易感性是至关重要的 成瘾和精神病，2)对大麻素的反应，3)对CanUD的新治疗方法的反应。 受到基因的强烈影响；我们发表了第一个CUD全基因组关联研究(GWAS)，与 全基因组--显著的结果；然而，遗传因素在 CUD的发展仍不明朗。大麻暴露也与一些精神病有关。 结果包括精神分裂症(SCZ)。SCZ是高度可遗传的，以群体为基础和遗传学研究 两者都支持SCZ和CanUD之间的双向遗传关系。然而，准确的贡献是 与大麻有关的精神病后果的发生中的遗传因素尚不清楚。 我们提出了一个翻译研究计划，将两个高生产率和互补性的 研究小组(遗传学[Gelernter]和大麻素药理学[D‘Souza])。1)我们将进行 CANUD全基因组关联分析和Meta分析计算CANUD的变异系数(CANUD-PRS) 基于最佳和最大可用数据集。这包括现有的和新的MVP、Allfus数据发布； 在项目过程中可获得的FinnGen和其他相关数据。我们将研究遗传学 在EA、AA和其他祖先群体中，CanUD与其他复杂性状的重叠和因果关系。2)我们还将 确定CANUD-PRS和SCZ-PRS对Δ-9-四氢大麻酚急性效应的影响程度 (THC)，人类实验室研究(HLS)中大麻的主要精神活性成分。最后，我们将探索 3a)CanUD-PRS预测对FAAH-抑制剂的反应的程度 治疗 以及CanUD的严重性 在完成的NIDA资助的试验中的预处理，以及3b)CANUD-PR和SCZ-PR分别影响 大麻衍生物在一项由退伍军人管理局资助的多中心大麻类药物前瞻性试验中的有效性和安全性。 这项研究的成功完成有望1)识别更多的CUD遗传风险基因座，2)在 欧洲人和非欧洲人，3)后Gwas统计分析，以了解 CUD，4)通过人体实验研究进行翻译，以增加我们对THC反应的了解 输注及其对大麻使用障碍和精神病发展的影响，以及5)遗传学 大麻使用障碍的新疗法和大麻类药物治疗对反应的影响 神经性疼痛。

Genetics of Cannabis Use Disorder and Cannabinoid Response In Humans Cannabis is widely used worldwide and is associated with negative outcomes including cannabis use disorder (CanUD), psychosis, and cognitive impairment amongst others. Given the legalization of “recreational” and “medical” cannabis globally, the increasing availability of cannabis, the higher potency of cannabis, the availability of highly potent cannabinoid products, the commercialization of cannabis, and the rising rates of cannabis use, it is critical to understand how genetic factors influence 1) an individual's vulnerability for addiction and psychosis, 2) the response to cannabinoids, 3) the response to novel treatments for CanUD.CUD is strongly genetically influenced; we published the first CUD genomewide association study (GWAS) with genomewide-significant results; however, the precise nature of the contribution of genetic factors in the development of CUD is still not clear. Cannabis exposure has also been linked to a number of psychosis outcomes including schizophrenia (SCZ). SCZ is highly heritable and population-based and genetics studies both support a bidirectional genetic relationship between SCZ and CanUD. However, the precise contribution of genetic factors in the development of psychosis outcomes related to cannabis are not clear. We propose a translational research program bringing together two highly productive and complementary research groups (genetics [Gelernter] and cannabinoid pharmacology [D'Souza]). 1) We will conduct a genomewide association analyses and meta-analyses of CanUD to compute PRS for CanUD (CanUD-PRS) based on best- and largest-available datasets. that includes existing and new data releases of MVP, AllofUs; FinnGen and other relevant data that becomes available over the course of the project. We will study genetic overlap and causality of CanUD with other complex traits in EA, AA, and other ancestry groups. 2) We will also determine the extent to which CanUD-PRS and SCZ-PRS influence the acute effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis in a Human Lab Study (HLS). Lastlywe will explore the extent to which 3a) CanUD-PRS predicts response to FAAH-Inhibitor treatment and also severity of CanUD pretreatment in a completed NIDA funded trial, and 3b) CanUD-PRS and SCZ-PRS, respectively influence the efficacy and safety of cannabis derivatives in a prospective large VA-funded multicenter trial with cannabinoids. Successful completion of this study is expected to 1) identify many more genetic risk loci for CUD, 2) in European and non-European populations, 3) with post-GWAS statistical analysis to understand the biologyof CUD, 4)translation via human experimental studies to increase our understanding of the response to THC infusion, and its implications for the development of cannabis use disorder and psychosis, and 5) the genetic influence on response to novel treatments for cannabis use disorder and cannabinoid treatments for neuropathic pain.