Date of Award
Doctor of Philosophy (PhD)
Aberrant reward-related behavior, including impulsive and risk-taking behaviors, is a common feature of externalizing psychopathology (e.g., attention deficit hyperactivity disorder, antisocial personality disorder, and substance-use disorders). Through imaging studies, these behaviors have been linked to dysregulated reactivity within a diffuse reward-related corticostriatal neural network, including the striatum, frontal regions (namely orbital, ventromedial, and dorsolateral cortices), the insula, and the hippocampus. Because variability in risk-taking behavior and related psychopathology is moderately-to-largely heritable (i.e., with estimates ranging from 40 – 80%), a genetically-informed approach is well-positioned to provide valuable insight into the etiology of reward-related neural and behavioral phenotypes that characterize externalizing psychopathology. Using summary statistics from a recent genome-wide association study (GWAS) of risk tolerance among 939,908 individuals, we generated polygenic risk scores (PRS) for a European-ancestry subsample (usable data ranging from n=457 to n=518; see Table 2) of the Duke Neurogenetics Study (DNS; a large community sample) and examined associations between genomic liability and risk-taking phenotypes (i.e., self-reported impulsivity and alcohol use, and behavioral delay discounting), as well as BOLD activation of the ventral striatum. Contrary to our hypotheses, GWAS-based PRS were not consistently significantly associated with risk-related behavior or with activation of the ventral striatum. In order to increase biological informativeness, we also used PrediXcan analyses to identify genes with differential expression based on the risk-related genomic liability; however, PRS of these differentially-expressed variants were also not significantly associated with risk-related behavioral or neural-activation phenotypes in the DNS. Though these null findings may reflect a true lack of association between risk-related genetic liability and behavior/neural externalizing phenotypes, we discuss possible alternative explanations regarding imprecise phenotyping in the discovery GWAS, inadequate statistical power, and questionable reliability of task-based fMRI measurements.
Chair and Committee
Todd Braver, Emma Johnson, Jonathan Peelle, Thomas Oltmanns,
Michalski, Lindsay Jane, "Genomic Contributors to Individual Differences in Reward-Related Neural Activity" (2019). Arts & Sciences Electronic Theses and Dissertations. 2010.