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，越来越多的人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CUDs是独特的临床实体，本申请寻求资金，对澳大利亚双胞胎及其非双胞胎兄弟姐妹的大量样本进行临床访谈，并进行全基因组连锁和个体全基因组关联扫描（WGAS），以检测CUDs的数量性状位点（QTL）。目标1：资助结构化临床访谈，以获得项目水平的数据和DSM-IV对1000名来自布里斯班青少年双胞胎样本的澳大利亚双胞胎及其非双胞胎兄弟姐妹的大麻滥用和依赖诊断。还将获得其他药物的项目水平数据和DSM-IV诊断，以及药物使用的终生模式、药物使用障碍和CUD表型的背景和发育风险因素的测量。使用K99中提出的相同的模型拟合策略（参见第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数据提供良好的拟合。目标2：利用460个家族的1000个个体的全基因组连锁分析，确定CUDs的qtl，然后对3000个个体进行个体WGAS分析。CUDs对个人造成的伤害和对社区造成的社会成本是巨大的。需要确定导致CUDs的qtl，以填补我们的知识空白，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注提供经验基础。通过利用美国和澳大利亚的数据，Gillespie博士还提出了一些极具成本效益的机会来测试新的研究问题和具体假设，这将提高我们对药物使用障碍的理解，作为未来分析的一部分。这将使我们能够确定CUDs的遗传易感性在多大程度上可以用导致其他药物使用障碍和/或精神障碍的相同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.