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

大麻使用障碍的遗传学和人类的大麻素反应 大麻在世界范围内广泛使用，并与包括大麻使用障碍在内的负面结果有关 （CanUD）、精神病和认知障碍等。鉴于“娱乐”合法化， 全球范围内的“医用”大麻，大麻供应量的增加，大麻的效力更高， 高效力大麻素产品的供应，大麻的商业化，以及 大麻使用，关键是要了解遗传因素如何影响1）个人的脆弱性， 成瘾和精神病，2）对大麻素的反应，3）对CanUD的新治疗的反应。 受到强烈的遗传影响;我们发表了第一个CUD全基因组关联研究（GWAS）， 全基因组显著的结果;然而，遗传因素在基因组中的贡献的确切性质， CUD的发展仍然不清楚。接触大麻也与一些精神病有关 结果包括精神分裂症（SCZ）。SCZ具有高度遗传性，且以人群为基础，遗传学研究 两者都支持SCZ和CanUD之间的双向遗传关系。然而， 与大麻有关的精神病结果的发展中的遗传因素尚不清楚。 我们提出了一个转化研究计划，将两个高效互补的 研究小组（遗传学[Gelernter]和大麻素药理学[D 'Souza]）。1)我们将进行 CanUD的全基因组关联分析和荟萃分析，以计算CanUD的PRS（CanUD-PRS） 基于最佳和最大的可用数据集。包括MVP、AllofUs的现有和新数据发布; FinnGen和其他在项目过程中可用的相关数据。我们将研究基因 CanUD与EA、AA和其他祖先群体中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影响Δ9-四氢大麻酚急性效应的程度 (THC)在人类实验室研究（HLS）中，大麻的主要精神活性成分。最后，我们将探讨 3a）CanUD-PRS预测对FAAH抑制剂的反应的程度 治疗 以及CanUD的严重程度 预处理完成NIDA资助的试验，和3b）CanUD-PRS和SCZ-PRS，分别影响 大麻衍生物的有效性和安全性在一个前瞻性的大型VA资助的多中心试验大麻素。 这项研究的成功完成预计将1）确定更多的CUD遗传风险位点，2） 欧洲和非欧洲人群，3）GWAS后统计分析，以了解 CUD，4）通过人体实验研究翻译，以增加我们对THC反应的理解 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 对大麻使用障碍和大麻素治疗新疗法反应的影响 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.