Neurostructural Correlates of IL-1β rs16944 Polymorphism in Adolescents with and without Bipolar Disorder by Daniel Oluwatobi Shonibare A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Pharmacology and Toxicology University of Toronto © Copyright by Daniel Oluwatobi Shonibare (2018) Neurostructural Correlates of IL-1β rs16944 Polymorphism in Adolescents with and without Bipolar Disorder Daniel Oluwatobi Shonibare Master of Science Department of Pharmacology and Toxicology University of Toronto 2018 Abstract Increased inflammation among youth with bipolar disorder (BD) is associated with increased illness severity. Functional inflammatory polymorphisms are associated with neurostructural changes in BD. This was examined for the first time in youth. T1-weighted images of 38 BD and 32 healthy controls (HCs) were processed through FreeSurfer to obtain cortical region of interest (ROI) volumes/surface area/thickness for dorsolateral prefrontal cortex and caudal anterior cingulate cortex, along with subcortical ROI volumes for hippocampus and amygdala. Our results show a main effect of interleukin (IL)-1β rs16944 in the lateral occipital cortex (LOC), along with a IL-1β rs16944-by-diagnosis interaction effect for a pars triangularis surface area cluster along with a LOC volume cluster. Our results suggest that the IL-1β rs16944 polymorphism is associated with neurostructural differences in youth with BD and HCs. Future studies including other imaging phenotypes and neurocognitive tasks are warranted to evaluate the relationship between IL-1β rs16944 and brain function. ii Acknowledgements I would like to express my sincerest gratitude and appreciation to my supervisor, Dr. Benjamin Goldstein, for his leadership, guidance, and support over the course of this research project. Dr. Goldstein has truly inspired me to be a better researcher through his excellent mentorship and has challenged me to broaden the scope of my scientific thinking. I appreciate the invaluable guidance he has given me throughout the duration of my schooling. I would also like to thank Dr. Bradley McIntosh and his research team for their neuroimaging knowledge and guidance. My appreciation also goes to all the graduate students and staff at the Centre for Youth Bipolar Disorder for their research support, personal support, and laughter. It was truly a blessing to be part of a team that is passionate about improving outcomes for adolescents with bipolar disorder. My experience at the Centre for Youth Bipolar Disorder was not just about acquiring an MSc degree, but leaving a lasting impact on many adolescents and their families. Lastly, I would like to give a special thanks to my family and friends who supported me through my studies. I am truly fortunate and blessed to have such an excellent support system. iii Table of Contents Acknowledgements .............................................................................................................. iii Table of Contents ................................................................................................................. iv List of Tables ........................................................................................................................ vi List of Figures...................................................................................................................... vii List of Abbreviations .......................................................................................................... viii 1. Introduction ........................................................................................................................1 1.1 Statement of Problem ...................................................................................................1 1.2 Purpose of Study and Objectives ..................................................................................3 1.3 Statement of Research Hypotheses and Rationale for Hypotheses ..............................4 1.4 Review of Literature .....................................................................................................5 1.4.1 Bipolar Disorder: Symptomology, Prevalence, and Burden .............................5 1.4.2 Neuroimaging in BD .........................................................................................7 1.4.3 Bipolar Disorder and Cardiovascular Disease .................................................11 1.4.4 Inflammation and Cardiovascular Disease ......................................................12 1.4.5 The Relationship between Inflammation and BD ...........................................13 1.4.6 Evidence of Anti-inflammatory Medications for BD ......................................16 1.4.7 Inflammatory Cytokine: IL-1β ........................................................................16 1.4.8 Summary of Literature and Rationale .............................................................18 2. Materials & Methods ........................................................................................................18 2.1 Study Design ..............................................................................................................18 2.2 Participant Selection ...................................................................................................19 2.2.1 Participant Recruitment ...................................................................................19 2.2.2 Inclusion Criteria .............................................................................................19 2.2.3 Exclusion Criteria ............................................................................................20 2.3 Study Schedule ...........................................................................................................20 2.4 Participant Demographics, Psychiatric, and Medical History ....................................21 2.5 Primary Interview Instruments ...................................................................................22 2.6 Anthropometric Data ..................................................................................................23 2.7 Genetic Data ...............................................................................................................23 2.7.1 Saliva Collection .............................................................................................23 2.7.2 Genotyping ......................................................................................................24 2.7.3 Hardy-Weinberg Equilibrium ..........................................................................25 2.8 Structural Imaging & Analysis ...................................................................................25 2.8.1 Image Acquisition ...........................................................................................25 2.8.2 Pre-processing Quality Control: T1 Rating......................................................25 2.8.3 Pre-processing and Surface Morphometry ......................................................26 2.8.4 Imaging Data Quality Control: Correcting Parcellation Errors .......................27 2.9 Defining Regions of Interest ......................................................................................29 2.10 Statistical Analyses ...................................................................................................30 2.11 Two-step Sensitivity Analyses .................................................................................31 2.12 Whole-brain Vertex-wise Exploratory Analyses ......................................................32 2.12.1 Characteristics of DOSS vs DODS Models ..................................................33 iv 2.13 Power Analysis .........................................................................................................34 3. Results ..............................................................................................................................34 3.1 Demographic and Clinical Characteristics .................................................................34 3.2 Hardy-Weinberg Calculation ......................................................................................35 3.3 ROI Analyses..............................................................................................................35 3.4 Sensitivity Analyses ...................................................................................................35 3.5 Whole-brain Vertex-wise Analyses ............................................................................40 4. Discussion.........................................................................................................................45 4.1 Summary of Findings .................................................................................................45 4.2 Interpretation of Findings ...........................................................................................46 4.2.1 Main Effect: The IL-1β rs16944 Polymorphism Effect in LOC Cluster .........46 4.2.2 Interaction Effect: Diagnosis by Polymorphism Effect in LOC Cluster .........47 4.2.3 Interaction Effect: Diagnosis by Polymorphism Effect in Pars Triangularis Cluster...................................................................................................................................48 4.3 Proposed Bottom-up Framework of the LOC ............................................................50 4.4 Cortical Surface