Date of Award
Doctor of Philosophy (PhD)
Externalizing spectrum disorders, which include attention-deficit/hyperactivity disorder, oppositional defiant disorder, conduct disorder, alcohol and substance use disorders, and antisocial personality disorder, are characterized by behavioral disinhibition and are thought to be manifestations of a common heritable liability factor throughout the lifespan. However, relatively little is known about their underlying etiology. Here, I probe genetic and neural risk mechanisms for externalizing psychopathology in three complementary studies. First, I report an indirect association between genetic risk for childhood attention-deficit/hyperactivity disorder (ADHD) and problem drinking in young adulthood, mediated by heightened reward-related neural activity within the ventral striatum, among 404 college students. I then provide additional support that such neural activity is a pre-existing risk factor for drinking behaviors by demonstrating that it prospectively predicts early versus late age-at-first-drink among 65 adolescents. Taken together, the results of these studies suggest that heightened reward-related ventral striatum activity is a genetically influenced neural risk marker for the initial stages of drinking behavior and is also related to ADHD genetic risk. Finally, I performed a genome-wide association study (GWAS) of retrospectively reported conduct disorder among 1675 Australian adults enriched for externalizing psychopathology, yielding novel genetic associations with rs12536973 at the single-variant level and GOLM1 at the gene level. In the sample of college students used in the first study, both rs12536973 genotype and genome-wide genetic risk calculated based on the results of the GWAS were associated with self-reported psychopathy constructs, and genome-wide genetic risk was additionally associated with blunted anterior insula activity during an emotional face-matching task. Overall, these findings identify potential neurogenetic mechanisms and risk markers for externalizing psychopathology and provide support for etiological relationships across disorders (e.g., ADHD and AUD/drinking behaviors), as well as between pathological and non-pathological externalizing variation (e.g., CD and individual differences in psychopathology among healthy college students).
Chair and Committee
Arpana Agrawal, Deanna M. Barch, Joshua J. Jackson, Douglas E. Williamson,
Carey, Caitlin E., "Neurogenetics of the Externalizing Spectrum" (2017). Arts & Sciences Electronic Theses and Dissertations. 1264.