In silico genome scan with high-throughput addiction related phenotypes in mice

描述（由申请人提供）：成瘾行为的进展被描述为一个涉及几个阶段的过程，从最初接触药物开始，然后是定期使用，最后是物质依赖或成瘾。成瘾研究传统上集中在最后阶段。近年来，越来越多的人对最初使用药物作为未来发展轨迹的决定因素感兴趣。被标记为失调、缺乏持久性、消化不良、感觉寻求、注意力不集中和奖励依赖的变量被认为是在初始阶段脆弱性增加的关键因素。不太完美的相互关联表明，这一集群可能缺乏单一的生物学基础。因此，必须确定构成最重要风险的具体方面。其中最有希望的候选人是冲动选择，其核心特征是对小的即时奖励的偏好，而不是较大的延迟奖励。从科学角度看，更好地了解其在吸毒初期阶段的作用将是重要的，并可能最终有助于预防和治疗。此外，作为基因和成瘾之间的中介结构，冲动选择可能是一种相关的内在表型，可能会导致更直接和成功的遗传分析。我们提出了一个小鼠研究。小鼠提供了收集数据的可能性，从而能够对药物使用的初始事件进行微观分析，由于伦理和实践的限制，在人类受试者中极难获得这些数据。此外，新的高质量公共资源将使人们有可能对致病性遗传变异进行“计算机模拟”全基因组扫描，而不需要进行任何基因分型。最后，表型和遗传对应表明，这种小鼠研究的结果将与人类相关。为了研究通路，动物实验通常涉及少量需要长时间集中观察的受试者。另一方面，遗传学研究关注的是受试者之间的差异如何影响需要大样本的结果。为了将这两个范例联系起来，我们提出了a）“高通量”表型分析程序，其可以从许多动物收集数据，同时仍然捕获有意义的过程信息，以及B）分析工具，其可以从具有理论解释的受试者内数据中提取指数，并且可以以受试者间的方式进行分析。

DESCRIPTION (provided by applicant): The progression towards addictive behavior has been described as a process involving several stages beginning with the initial contact with the drug, followed by its regular use, and finally substance dependence or addiction. Addiction research has traditionally concentrated on the final stages. Recently yeas has shown more interest in initial drug use as a determinant of future developmental trajectories. Variables labeled with terms as dysregulation, lack of persistence, dysinhibition, sensation seeking, inattention, and reward dependence have been postulated as a key factor underlying heightened vulnerability during the initial stages. The less than perfect intercorrelations suggest that this cluster may lack a single biological basis. It is therefore important to identify the specific dimension that constitutes the most important risk. Among the most promising candidates is impulsive choice of which the core feature is a preference for small immediate rewards rather than larger delayed rewards. A better understanding of its role in the initial stages of drug use will be important from a scientific perspective and may eventually contribute to prevention and treatment. Furthermore, as a construct mediating between genes and addiction, impulsive choice could be a relevant endophenotype that may result in more straightforward and successful genetic analyses. We propose a mouse study. Mice offer the possibility to collect data enabling a micro-analysis of initial episodes of drug use that, due to ethical and practical constraints, would be extremely difficult to obtain in human subjects. Furthermore, new high quality public resources will make it possible to perform an "in silico" whole-genome scan for causal genetic variants without the need for any genotyping. Finally, phenotypic and genetic correspondence suggests that results from such a mouse study will be relevant for humans. To study pathways, animal experiments usually involve a small number of subjects that need to be observed intensively over long periods of time. Genetic studies, on the other hand, focus on how variation between subjects affects the outcomes of interest requiring large samples. To link these two paradigms we propose a) "high-throughput" phenotyping procedures that can collect data from many animals while still capturing meaningful process information, and b) analytical tools that can extract indices from the within-subject data that have a theoretical interpretation and can be analyzed in a between-subject fashion.