Author ORCID Identifier
https://orcid.org/0000-0003-0170-2242
Defense Date
2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Integrative Life Sciences
First Advisor
Michael C. Neale, Ph.D.
Second Advisor
Ananda B. Amstadter, Ph.D.
Abstract
Abstract
QUANTITATIVE AND MOLECULAR GENETIC ANALYSES OF BRAIN-IMAGING, SUBSTANCE USE, AND POSTTRAUMATIC STRESS PHENOTYPES: DATA FROM CHILDREN, ADOLESCENTS AND ADULTS
By Daniel Bustamante, B.S., B.A.
Doctoral dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Integrative Life Sciences – Behavioral and Statistical Genetics at Virginia Commonwealth University.
Virginia Commonwealth University, 2023.
Dissertation directors: Michael C. Neale, Ph.D., Banks Distinguished Professor of Psychiatry & Human and Molecular Genetics; and, Ananda B. Amstadter, Ph.D., Professor of Psychiatry, Psychology, & Human and Molecular Genetics.
Substance use (SU) and posttraumatic stress disorder (PTSD) phenotypes are comorbid, share etiologies, and are associated with differences in brain volumes, cortical thickness and surface area. Genetic and environmental factors influence the variation and covariation of these phenotypes. Most of the research investigating these phenotypes and their associations has assessed adult samples. I extended this work to children and adolescents using the Adolescent Brain Cognitive Development (ABCD) Study® data from baseline, 1-year, and 2-year follow-up (1yFU, 2yFU) release (N=11,876, Mage=9.92; N=11,225, Mage=10.92; N=10,414, Mage=12.00, respectively). Structural equation modeling (SEM) and an elastic-net (EN) machine-learning approach were used to select, out of 776 brain regions[1], those that most associated with traumatic events (TEs) and PTSD symptoms (PTSDsx; Aim 1), TEs and PTSDsx, quantity of alcohol sips and maximum intake of caffeinated drinks in youth (Aim 2 and 3). I then estimated the phenotypic, genetic and environmental variation and covariation of these phenotypes. Additionally, using genome-wide association studies summary data, I also calculated the polygenic risk scores (PRSs) for alcohol dependence (AD), alcohol use disorder (AUD), alcohol-use problems, cannabis-use disorder (CUD), cigarettes per day (CPD), and PTSD. After this calculation, I assessed the associations of these PRSs with TEs, PTSDsx, alcohol sipping, maximum intake of caffeinated drinks, and structural brain-MRI phenotypes via SEM and maximum likelihood estimation.
TEs were directly associated with PTSDsx (r=0.92) in children, but their indirect effects (r<0.0004)—via the volumes of EN-identified subcortical and cortical ROIs—were negligible for children aged 9-10. Additive-genetic factors explained a modest proportion of the variance in TEs (23.4%) and PTSDsx (21.3%), and accounted for most of the variance of EN-identified volumes of four of the five subcortical (52.4%-61.8%) three of the nine cortical ROIs (46.4%-53.3%) and cerebral white matter in the left hemisphere (57.4%). Environmental factors explained most of the variance in TEs (C=61.6%, E=15.1%), PTSDsx (residual-C=18.4%, residual-E=21.8%), right lateral ventricle (C=15.2%, E=43.1%) and six of the nine EN-identified cortical ROIs (C=4.0%-13.6%, E=56.7%-74.8%). TEs, PTSDsx, alcohol sipping, and maximum intake of caffeinated drinks had low to moderate phenotypic associations (Baseline=-0.15 to 0.41; 2yU=-0.11 to 0.32) with EN-selected cortical regions’ SAs. The additive-genetic correlations (rAs) between the SA of EN-selected contralateral-homologous regions were positive, moderate to high (Baseline: 0.56 (-0.046
Conclusions: Evidence from this study show that for children 9-10 years of age, the indirect associations of TEs with PTSDsx via the volumes of brain regions are negligible. Generally, environmental factors accounted for more of the variation in TEs and PTSDsx; whereas, additive-genetic factors influenced most of the variation in the volumes of a minority of cortical and in most of subcortical regions. Findings from this dissertation study support that shared-genetic factors have a substantial influence on the bilateral symmetry of cortical surface area of brain regions that most associate with trauma, PTSD, and substance-related phenotypes in youth. The strong influence of shared-genetic factors can be seen in the covariation of the surface area of EN-selected adjacent regions compared to those between more distal regions. There is also evidence for a transitional anterior-posterior gradient clustering of adjacent cortical regions based on shared-genetic factors of cortical surface area. Clustering of adjacent or neighboring EN-selected regions opposed to more distal regions, can also be observed based on specific environmental sources of covariation. Lastly, findings from this dissertation study show a pattern of variation in the structure of multiple neighboring and adjacent parietal and occipital brain regions (mostly in the right hemisphere) linked to greater polygenic risk for alcohol, cannabis and cigarette use phenotypes. Conversely, PTSD polygenic risk associated with a frontal region. The polygenic risk for CUD may be linked differently with higher quantities of alcohol sips and caffeine intake in youth, depending on their age.
[1] The number of brain regions varied depending on each of the three studies in this dissertation study (Aim-1 study: 300 subcortical and cortical regions of volume; Aim-2 study: 245 cortical regions of surface area; Aim-3 study: 776 subcortical and cortical brain regions of volume, cortical thickness and surface area).
Rights
© Daniel Bustamante
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-8-2024