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.

人类中大麻使用障碍和大麻素反应的遗传学 大麻在全球范围内广泛使用，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。鉴于“娱乐”合法化和 全球“医疗”大麻，大麻的可用性增加，大麻的效力较高， 高潜在的大麻素产品的可用性，大麻的商业化以及上升的速度 大麻使用，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.cud的新疗法的反应 受到强烈的遗传影响；我们发表了第一项与GENOMEWIDE协会研究（GWAS）的 全基因组相关的结果；但是，遗传因素在 CUD的发展仍然不清楚。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。 SCZ是高度可遗传的，基于人群和遗传学研究 两者都支持SCZ和Canud之间的双向遗传关系。但是，精确的贡献 与大麻有关的精神病发展发展中的遗传因素尚不清楚。 我们提出了一项翻译的研究计划，将两个高产和完善的工作融合在一起 研究小组（遗传学[Gelernter]和大麻素药理学[D'Souza]）。 1）我们将进行 Canud的全基因组关联分析和荟萃分析，以计算Canud（Canud-prs）的PR 基于最佳和最大可用数据集。其中包括MVP，Allofus的现有和新数据发布； 在项目过程中可用的Finngen和其他相关数据。我们将研究遗传 Canud与EA，AA和其他祖先组中其他复杂性状的重叠和因果关系。 2）我们也会 确定Canud-PRS和SCZ-PR在多大程度上影响Δ9-四氢大麻酚的急性影响 （THC），主要的精神活性构成了人类实验室研究（HLS）的大麻。最后，我们将探索 3a）Canud-prs预测对FAAH抑制剂的响应的程度 治疗 也是卡特的严重性 在一项完整的NIDA资助试验中进行预处理，以及3B）Canud-PR和SCZ-PR，分别影响 大麻衍生物的功效和安全性在一项由大麻素的前瞻性大型VA资助的多中心试验中。 预计这项研究的成功完成为1）确定CUD的更多遗传风险基因座，2） 欧洲和非欧洲人口，3）与GWAS后统计分析一起了解生物学 CUD，4）通过人类实验研究的翻译，以增加我们对THC反应的理解 输液及其对大麻使用障碍和精神病发展的影响，以及5）通用 对大麻使用障碍和大麻素治疗的新型治疗的反应的影响 神经性疼痛。