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

描述（由申请人提供）：成瘾行为的发展被描述为一个包括几个阶段的过程，从最初接触药物开始，然后是常规使用，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，人们对最初的药物使用作为未来发展轨迹的决定因素表现出了更多的兴趣。被标记为调节失调、缺乏毅力、抑制障碍、寻求感觉、注意力不集中和奖励依赖的变量被认为是在初始阶段潜在的高度脆弱性的关键因素。这种不太完美的相互关系表明，这种群集可能缺乏单一的生物学基础。因此，重要的是确定构成最重要风险的具体方面。其中最有希望的是冲动选择，其核心特征是偏好小的即时奖励，而不是大的延迟奖励。从科学的角度来看，更好地了解它在吸毒初期的作用是很重要的，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表型，可能导致更直接和成功的遗传分析。我们提议进行小鼠研究。小鼠提供了收集数据的可能性，可以对最初的药物使用情况进行微观分析，由于伦理和实际限制，在人类受试者中很难获得这些数据。此外，新的高质量公共资源将使在不需要任何基因分型的情况下，对因果遗传变异进行“计算机”全基因组扫描成为可能。最后，表型和遗传对应表明，这样的小鼠研究结果将适用于人类。为了研究通路，动物实验通常只涉及少量的实验对象，需要长时间的集中观察。另一方面，基因研究关注的是受试者之间的差异如何影响需要大样本的研究结果。为了将这两种范式联系起来，我们提出了a)“高通量”表型分析程序，可以从许多动物身上收集数据，同时仍然捕获有意义的过程信息；b)分析工具，可以从具有理论解释的主题内数据中提取指标，并可以以主题之间的方式进行分析。

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.