Genetic & environmental pathways to drug use, abuse & dependence

描述(由申请人提供)：该项目的目标是为发现影响大麻使用障碍(CUD)的基因做出重大贡献。鉴于大麻的广泛使用，人们越来越多地认识到这种药物对健康的潜在影响，以及越来越多的人认识到CUD是不同的临床实体，这项申请寻求资金，以对澳大利亚双胞胎及其非双胞胎兄弟姐妹进行大样本临床访谈，并运行全基因组链接和个人基因组全关联扫描(WGAs)来检测CUD的数量特征基因座(QTL)。具体目标是：目标1：资助结构化临床访谈，以便从布里斯班青少年双胞胎样本中获得关于1000对澳大利亚双胞胎及其非双胞胎兄弟姐妹滥用大麻和依赖的项目级数据和DSM-IV诊断。还将获得其他药物的项目级数据和DSM-IV诊断，以及对药物使用的终身模式、药物使用障碍以及CUD表型的背景和发展风险因素的测量。使用K99中建议的相同模型拟合策略(见第4.D.3.2.4节)，这些数据将使我们能够确定基于MATR数据的最佳拟合经验CUD表型是否与澳大利亚的数据很好地匹配。目标2：使用基于来自460个家庭的1000个个体的全基因组连锁分析来识别CUD的QTL，然后对3000个个体进行WGA分析。CUDS对个人造成的损害和对社会造成的社会成本是巨大的。需要确定导致大麻使用障碍的QTL，以填补我们知识上的空白，开发有针对性的治疗方法，并为解决政策问题和公众对大麻使用障碍原因的关切提供经验基础。通过利用美国和澳大利亚的数据，吉莱斯皮博士还建议，作为未来分析的一部分，提供一些极具成本效益的机会来测试新的研究问题和具体的假设，这将提高我们对药物使用障碍的理解。这将使我们能够确定对CUD的遗传责任在多大程度上可以由负责其他药物使用障碍和/或精神障碍的责任的相同QTL来解释。

DESCRIPTION (provided by applicant): The goal of this project is to make a significant contribution to the discovery of genes influencing cannabis use disorders (CUD). Given the widespread use of cannabis, increasing recognition of the potential health effects of this drug, and a growing recognition of CUDs as distinct clinical entities, this application seeks funding to conduct clinical interviews on a large sample of Australian twins and their non-twin siblings, and run genome wide linkage and individual genome wide association scan (WGAS) to detect quantitative trait loci (QTL) for CUDs. The specific aims are: Aim 1: To fund structured clinical interviews in order to obtain item level data and DSM-IV diagnoses of cannabis abuse and dependence on 1000 Australian twins and their non-twin siblings from the Brisbane Adolescent Twin Sample. Item level data and DSM-IV diagnoses for other drugs, as well as measures of lifetime patterns of drug use, drug use disorders, and contextual and developmental risk factors for CUD phenotypes will also be obtained. Using the same model fitting strategy proposed in the K99 (see Section 4.D.3.2.4), these data will allow us to determine whether the best fitting empirical CUD phenotypes based on MATR data, provide a good fit to the Australian data.; Aim 2: Identify QTLs for CUDs using genome wide linkage analyses based on 1000 individuals from 460 families, followed by individual WGAS analyses on 3000 individuals. The damage to individuals and the social cost to the community caused by CUDs are enormous. The identification of QTLs responsible for CUDs is required to fill gaps in our knowledge, to develop targeted treatments, and to provide an empirical basis for addressing policy issues and public concerns about the cause of cannabis use disorders. By capitalizing on the US and Australian data, Dr Gillespie is also proposing, as part of future analyses, a number of enormously cost-effective opportunities to test novel research questions and specific hypotheses which will improve our understanding of drug use disorders. These will enable us to determine the degree to which genetic liability to CUDs can be explained by the same QTLs responsible for liability to other drug use disorders and/or psychiatric disorders.