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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Risk, Prevention and Intervention for Addictions Study Section (RPIA)
Program Officer
Gordon, Harold
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University of Chicago
Schools of Medicine
United States
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Hart, Amy B; Gamazon, Eric R; Engelhardt, Barbara E et al. (2014) Genetic variation associated with euphorigenic effects of d-amphetamine is associated with diminished risk for schizophrenia and attention deficit hyperactivity disorder. Proc Natl Acad Sci U S A 111:5968-73
Weafer, Jessica; de Wit, Harriet (2014) Sex differences in impulsive action and impulsive choice. Addict Behav 39:1573-9
Wardle, M C; Hart, A B; Palmer, A A et al. (2013) Does COMT genotype influence the effects of d-amphetamine on executive functioning? Genes Brain Behav 12:13-20
Weafer, Jessica; de Wit, Harriet (2013) Inattention, impulsive action, and subjective response to D-amphetamine. Drug Alcohol Depend 133:127-33
MacKillop, James (2013) Integrating behavioral economics and behavioral genetics: delayed reward discounting as an endophenotype for addictive disorders. J Exp Anal Behav 99:14-31
de Wit, Harriet; Phillips, Tamara J (2012) Do initial responses to drugs predict future use or abuse? Neurosci Biobehav Rev 36:1565-76
Palmer, Abraham A; de Wit, Harriet (2012) Translational genetic approaches to substance use disorders: bridging the gap between mice and humans. Hum Genet 131:931-9