Delineating the Role of Genetic Influences on Cannabis Involvement

描述（由申请人提供）：这个独立科学家职业发展（K02）申请的总体目标是支持具有成瘾专业知识的定量遗传学家候选人的持续职业发展，并通过整合双胞胎流行病学，候选基因和全基因组关联研究的方法，促进她努力建立一个研究计划，研究遗传影响对大麻参与的作用。大麻是发达国家最常用的非法药物，在过去两年中，大麻的使用和滥用都有所增加。然而，人们对其基因基础知之甚少。候选人正在进行的工作描述了潜在的（通过对双胞胎数据的分析）和测量的（通过联系、候选基因和全基因组关联）遗传影响如何影响对大麻的脆弱性。本建议以现有框架为基础，纳入以下方面的培训：(a)内源性大麻素药理学；(b)将药理学证据与人类遗传学研究相结合的多元统计方法；(c)遗传影响与治疗相关结果的相关性，使候选人能够在具有生物学相关性和统计意义的背景下，重新编写关于吸食大麻的遗传流行病学的现有文献。与专家的跨学科合作以及将新获得的知识应用于正在进行的数据分析将使该K02大大扩展我们对大麻参与遗传学的现有知识。从心理健康的角度来看，这项建议的发现解决了大麻使用率不断上升所带来的挑战的一个关键组成部分——遗传途径如何形成其病因。他们有可能提供对大麻参与的生物学基础的精确理解，同时研究其在治疗环境中的相关性。本提案的具体目标是：(a)使用孪生模型来描述遗传影响对从有机会使用大麻到发展为大麻使用障碍的大麻使用阶段的作用；(b)利用内源性大麻素药理学知识，确定大麻参与的哪些具体方面与候选基因（例如CNR1）相关；(c)使用新颖的统计方法进行和有效地解释全基因组关联研究；(d)将先前目标的发现应用于治疗环境，并描述基因组风险对治疗结果的作用。该K02还将支持候选人的愿景，即通过提供特定于成瘾相关表型的方法培训，为下一批成瘾研究人员提供指导。

DESCRIPTION (provided by applicant): The overall objective of this Independent Scientist Career Development (K02) application is to support the continued career development of the candidate who is a quantitative geneticist with specialized expertise in addiction and to facilitat her efforts to build a program of research into the role of genetic influences on cannabis involvement by integrating methodologies from twin epidemiological, candidate gene and genomewide association studies. Cannabis is the most commonly used illicit drug in developed nations and both cannabis use and misuse have undergone increase in the past 2 years. Yet, far too little is known of its genetic underpinnings. Ongoing work by the candidate has delineated how latent (via analysis of twin data) and measured (via linkage, candidate gene and genomewide association) genetic influences shape vulnerability to cannabis involvement. This proposal builds on that existing framework by incorporating training in (a) endocannabinoid pharmacology; (b) multivariate statistical methods that integrate pharmacological evidence with human genetics studies; and (c) the relevance of genetic influences on treatment-related outcomes, to allow the candidate to recast the extant literature on the genetic epidemiology of cannabis involvement in a biologically relevant and statistically meaningful context. Cross-disciplinary collaboration with experts and application of newly acquired knowledge to ongoing data analysis will allow this K02 to significantly expand on our existing knowledge of the genetics of cannabis involvement. From a mental health perspective, findings from this proposal address a key component of the challenges imposed by escalating rates of cannabis use - how genetic pathways shape its etiology. They have the potential to provide a refined understanding of the biology underlying cannabis involvement while simultaneously studying its relevance in treatment settings. The specific goals of this proposal are to (a) use twin modeling to delineate the role of genetic influences on stages of cannabis involvement from opportunity to use to the development of cannabis use disorders; (b) use knowledge from endocannabinoid pharmacology to identify which specific aspects of cannabis involvement are associated with candidate genes (e.g. CNR1); (c) to use novel statistical methods to conduct and efficiently interpret genomewide association studies; and (d) to apply the findings from prior aims to treatment settings and delineate the role of genomic risk on treatment outcomes. This K02 will also support the candidate's vision to provide mentorship to the next cohort of addiction researchers through provision of training in methodologies specific to addiction-related phenotypes.