Author ORCID Identifier
0000-0003-1115-0314
Defense Date
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Human and Molecular Genetics
First Advisor
Michael Miles
Second Advisor
Jill Bettinger
Third Advisor
Imad Damaj
Fourth Advisor
Jolene Windle
Fifth Advisor
Timothy York
Abstract
As a complex genetic disorder, alcohol use disorder (AUD) is thought to be influenced by many genes each contributing only a small effect to the overall disease liability. Dozens of genes have been implicated as potentially affecting risk for AUD and alcohol consumption. However, understanding the full genetic architecture of AUD – what genes are involved, to what extent, and how these genes are regulated – remains a challenging step in identifying novel treatments. Gene expression studies in humans have attempted to augment GWAS of alcohol consumption but are often confounded by environmental factors; the difficulty of collecting tissue from brain regions relevant to AUD, such as the prefrontal cortex (PFC) and nucleus accumbens (NAc); and the correlational nature of most transcriptomics studies. In this series of studies, we utilize a novel mouse model (the Diversity Outbred mouse) to map genetic loci influencing voluntary alcohol consumption, then characterize gene expression patterns in the PFC and NAc to identify candidate genes for further study. We apply a systematic, machine-learning based approach to harmonize data across multiple transcriptomics analyses in NAc, followed by using structural equation modeling techniques to identify genes likely to be modulating ethanol consumption. Finally, we identify a candidate gene, carbonic anhydrase 8 (Car8), as a mediator of ethanol consumption through gene expression in PFC and validate these approaches through viral-mediated knockout of Car8 in mPFC, demonstrating an increase in voluntary ethanol consumption among male mice. These results highlight the utility of Diversity Outbred mice in mapping the genetic architecture of traits, demonstrate the use of transcriptomics analyses to form discrete and testable hypotheses following genomics studies, and suggest an important role for expression of Car8 in PFC in modulating voluntary ethanol consumption.
Rights
© Zachary Tatom
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
9-26-2024