ORCID

http://orcid.org/0000-0001-5660-4805

Date of Award

Winter 12-15-2019

Author's School

Graduate School of Arts and Sciences

Author's Department

Psychology

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

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.

Language

English (en)

Chair and Committee

Ryan Bogdan

Committee Members

Todd Braver, Emma Johnson, Jonathan Peelle, Thomas Oltmanns,

Comments

Permanent URL: https://doi.org/10.7936/k9yq-mz05

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