The genetic basis of impulsive behavior in humans

描述(申请人提供)：本项目将研究冲动行为的潜在因素结构，并调查健康人类志愿者冲动行为的遗传基础。冲动行为与药物滥用风险密切相关，并被认为在一定程度上是由遗传因素决定的。在这里，研究人员将使用标准化的行为任务来检验冲动行为的两个主要组成部分：冲动选择(不适应决策)和冲动行动(即行为抑制)。他们将根据受试者在任务中的表现经验地推导出结构，然后检查被认为是导致结构变化的基因的多态。研究人员将重点研究影响多巴胺系统功能的基因。该项目解决了从行为上定义冲动的潜在组成部分以及确定影响变异性的遗传因素的迫切需要。这些发现将帮助我们理解冲动行为，这是吸毒的关键风险因素或中间表型。首先，我们将在精心选择的冲动选择和冲动行动的行为指标上对健康的无关年轻人(N=1,000)进行表型，并确定构成这些不同行为的因素。参与者将接受两次最大可靠性测试，我们将使用因子分析来确定潜在的潜在因素。其次，我们将在三个层次的分析中检查衍生因子与多巴胺和其他选定基因类型的遗传变异之间的关系。使用候选基因方法，我们将重点研究特定与多巴胺功能相关的选定基因的多态。我们假设，导致多巴胺功能低下的基因类型将与更高的冲动行为相关。使用基于途径的方法，我们将在已发表的文献的基础上研究更大的一组感兴趣的基因的多态。最后，使用一种无假设的方法，我们将检查大约100万个多态，这些多态将调查基因组中的所有基因。因此，我们将包括假设检验和探索性方法，以全面检查冲动的遗传基础。该项目意义重大，因为它将促进对冲动行为及其遗传基础的理解，这与药物滥用的风险直接相关。这项研究具有创新性，因为它结合了严格的行为分析和多层次的遗传分析。 公共卫生相关性：冲动是造成与药物使用和滥用有关的问题的主要风险因素之一。在决策情况下难以自我控制，或难以抑制不当行为的人，更有可能尝试药物，并进展到过度使用。在这个项目中，我们将研究这些冲动行为的遗传基础。健康的志愿者将完成测量不同形式冲动行为的有效任务，然后将检查他们的表现与被认为控制这些行为的选定基因的关系。这项研究将有助于我们了解冲动行为的潜在因素结构，以及遗传因素对这些行为的影响程度。

DESCRIPTION (provided by applicant): This project will examine the underlying factor structure of impulsive behaviors, and investigate the genetic basis of impulsive behaviors in healthy human volunteers. Impulsive behaviors are strongly implicated in risk for drug abuse, and are thought to be determined in part by genetic factors. Here, the investigators will examine the two main components of impulsive behavior: Impulsive Choice (maladaptive decision-making) and Impulsive Action (i.e., behavioral inhibition) using standardized behavioral tasks. They will empirically derive constructs based on subjects' performance on the tasks, and then examine polymorphisms in genes thought to contribute to variations in the constructs. The investigators will focus on genes that affect function of the dopamine system. The project addresses an urgent need to define behaviorally the underlying components of impulsivity, and to identify genetic factors that influence variability. The findings will help us understand impulsive behaviors, which are key risk factors, or intermediate phenotypes, for drug use. First, we will phenotype healthy unrelated young adults (N=1,000) on carefully selected behavioral measures of Impulsive Choice and Impulsive Action, and identify the factors comprising these heterogeneous behaviors. Participants will be tested twice for maximum reliability, and we will use factor analysis to identify the underlying latent factors. Second, we will examine associations between the derived factors and genetic variation in dopamine and other selected genotypes, in three levels of analysis. Using a candidate gene approach, we will focus on polymorphisms in selected genes related specifically to dopamine function. We hypothesize that genotypes resulting in low dopamine function will be associated with higher impulsive behaviors. Using a pathway-based approach, we will investigate polymorphisms in a larger set of genes of interest based on the published literature. Finally, using a hypothesis-free approach, we will examine ~1 million polymorphisms that will survey all the genes in the genome. Thus, we will include both hypothesis testing and exploratory approaches to comprehensively examine the genetic basis of impulsivity. The project is significant because it will advance understanding of impulsive behavior and its genetic underpinnings, which has direct relevance to risk for substance abuse. The study is innovative because it combines rigorous behavioral analysis with multi-level genetic analysis. PUBLIC HEALTH RELEVANCE: One of the primary risk factors for developing problems related to drug use and abuse is impulsivity. Individuals who have difficulty either exerting self-control in decision-making situations, or inhibiting inappropriate behaviors, are more likely to experiment with drugs and progress to excessive use. In this project we will investigate the genetic basis of these impulsive behaviors. Healthy volunteers will complete validated tasks measuring different forms of impulsive behaviors, and their performance will then be examined in relation to selected genes thought to control these behaviors. This study will help us to understand the underlying factor structure of impulsive behavior, and the degree to which genetic factors contribute to these behaviors.