The genetic basis of impulsive behavior in humans

项目描述（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的风险密切相关，并被认为部分由遗传因素决定。在这里，研究人员将研究冲动行为的两个主要组成部分：冲动选择（适应不良的决策）和冲动行为（即，行为抑制）使用标准化行为任务。他们将根据受试者在任务中的表现经验性地推导出结构，然后检查被认为有助于结构变化的基因多态性。研究人员将重点关注影响多巴胺系统功能的基因。该项目解决了迫切需要定义行为冲动的基本组成部分，并确定影响变异的遗传因素。这些发现将帮助我们理解冲动行为，这是药物使用的关键风险因素或中间表型。首先，我们将表型的健康无关的年轻人（N=1,000）仔细选择的冲动选择和冲动行为的行为措施，并确定这些异质性行为的因素。参与者将接受两次测试，以获得最大的可靠性，我们将使用因素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研究衍生因素与多巴胺和其他选定基因型遗传变异之间的关联。使用候选基因的方法，我们将专注于特定的多巴胺功能相关基因的多态性。我们假设导致多巴胺功能低下的基因型将与更高的冲动行为相关。使用基于途径的方法，我们将研究多态性在一个更大的一组感兴趣的基因的基础上发表的文献。最后，使用无假设的方法，我们将检查约100万个多态性，这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的方法来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，这与药物滥用风险直接相关。这项研究是创新的，因为它结合了严格的行为分析和多层次的遗传分析。

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.