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

人类接触大麻的风险和后果的遗传基础

• 批准号: 10720412
• 负责人: DEEPAK Cyril D'SOUZA
• 金额: $ 58.91万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720412
• 关键词: Acute; Attention; Biology; Cannabidiol; Cannabinoids; Cannabis; Clinical; Clinical Trials; Cognitive; Complex; DSM-V; Data; Data Pooling; Data Set; Development; Double-Blind Method; Etiology; European; FAAH inhibitor; Funding; Genetic; Genetic Risk; Genetic study; Genomics; Heritability; Human; Impaired cognition; Impairment; Infusion procedures; Investigation; Laboratory Study; Legal; Link; London; Maps; Medical Marijuana; Memory; Mendelian randomization; Meta-Analysis; Methodology; Methods; Multicenter Trials; National Institute of Drug Abuse; Nature; Outcome; Pain; Pathogenesis; Pharmacology; Phenotype; Placebo Control; Population; Productivity; Psychiatry; Psychoses; Publishing; Randomized; Recreation; Research; Rewards; Risk; Safety; Sampling; Schizophrenia; Services; Severities; Statistical Data Interpretation; Tetrahydrocannabinol; Translations; Veterans; Vulnerable Populations; Work; addiction; cannabinoid administration; cannabinoid treatment; commercialization; disorder risk; experimental study; genome wide association study; genome-wide; human subject; improved; marijuana use; marijuana use disorder; marijuana user; novel; painful neuropathy; polygenic risk score; population based; predicting response; programs; prospective; psychiatric genomics; response; risk variant; side effect; trait; translational research program; whole genome

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.

人类大麻使用障碍和大麻素反应的遗传学 大麻在世界范围内广泛使用，并与大麻使用障碍等负面后果相关 （CanUD）、精神病和认知障碍等。 全球范围内的“医用”大麻、大麻的供应量不断增加、大麻的效力更高、 高效大麻素产品的可用性、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 1) 个人的脆弱性至关重要 成瘾和精神病，2) 对大麻素的反应，3) 对 CanUD.CUD 新疗法的反应 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) 然而，遗传因素在基因组范围内的贡献的确切性质 CUD 的发展仍不清楚。大麻暴露也与许多精神病有关。 包括精神分裂症 (SCZ) 在内的结果是高度遗传的、基于人群的遗传学研究。 两者都支持 SCZ 和 CanUD 之间的双向遗传关系。 与大麻相关的精神病结果发展中的遗传因素尚不清楚。 我们提出了一项转化研究计划，将两个高效且互补的项目结合在一起 研究小组（遗传学 [Gelernter] 和大麻素药理学 [D'Souza]） 1) 我们将进行一项研究。 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 的现有和新数据版本； FinnGen 和项目过程中可用的其他相关数据我们将研究遗传。 CanUD 与 EA、AA 和其他祖先群体中其他复杂特征的重叠和因果关系 2) 我们还将。 确定 CanUD-PRS 和 SCZ-PRS 对 Δ9-四氢大麻酚急性作用的影响程度 （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讨。 3a) CanUD-PRS 预测对 FAAH 抑制剂反应的程度 治疗 以及 CanUD 的严重性 已完成的 NIDA 资助试验中的预处理，以及 3b) CanUD-PRS 和 SCZ-PRS 分别影响 在一项由 VA 资助的前瞻性大型大麻素多中心试验中，大麻衍生物的功效和安全性。 这项研究的成功完成预计将 1) 确定更多 CUD 遗传风险位点，2) 欧洲和非欧洲人群，3) 通过 GWAS 后统计分析来了解生物学 CUD，4）通过人体实验研究进行翻译，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 对大麻使用障碍新疗法和大麻素治疗反应的影响 神经性疼痛。