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Genomic stratification of bipolar disorder trajectories and outcome

Primerano, Amedeo 2023. Genomic stratification of bipolar disorder trajectories and outcome. PhD Thesis, Cardiff University.
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The intricate interplay between disease trajectories, outcomes, and the underlying genomic structure represents a complex and significant issue within the realm of bipolar disorder. The primary objective of this thesis is to make a valuable contribution to the field by investigating and providing insights into this complex interrelationship. The thesis is organized into three distinct sections, with the first two focusing on the definition of the phenotype and the third section delving into the genomic structure that influences and predicts the observed phenotypes. Before the three sections, the background chapter delved into the clinical presentation of bipolar disorder, mood instability, and Polygenic Risk Scoring in neuropsychiatry, with a specific focus on bipolar disorder. Integral to all subsequent analyses is a comprehensive review of existing literature, examining outcomes in bipolar disorder. The review commenced by addressing the necessity to define and individualize the selection of potential outcomes in bipolar disorder. Subsequently, all subsequent analyses were substantially influenced by the definitions and findings uncovered in this review. In the first section, the analysis involved a longitudinal study comprising 1,020 individuals diagnosed with bipolar disorder. By examining the weekly registered data, novel phenotypic variables were derived to describe the proportion of time individuals experienced specific mood symptomatology. Notably, individuals with bipolar 2 disorder exhibited a significantly higher mean total proportion of time spent with mood symptoms and depressive symptoms compared to individuals with bipolar 1 disorder. Additionally, the retrospective assessment of episode frequency showed a significant correlation with the proportion of time spent ill during the prospective follow-up for both bipolar disorder subtypes. Moving to the second section, disease outcomes were investigated utilizing a factor analysis approach on retrospective data from a cohort of 3,505 individuals diagnosed with bipolar disorder. The exploratory factor analysis revealed a five-factor structure for bipolar 1 disorder and a four-factor structure for bipolar 2 disorder, explaining 66% and 56.5% of the variance, respectively. Each factor captured specific aspects of the disorder, including social functioning (e.g., employment and educational achievements), severity of the disorder, hospital admissions, and characteristics of mood episodes. The utilization of factor analysis allowed for a more comprehensive understanding of the bipolar disorder phenotype by identifying and describing these distinct dimensions of outcomes. The third section focused on investigating the genomic structure underlying the complex phenotypes observed in the previous two sections, utilizing Polygenic Risk Scoring (PRS). Multiple PRSs for various neuropsychiatric traits were generated and analysed. In the longitudinal study, significant associations were found between the proportion of time spent ill and with depressive symptoms, and PRSs for Depression, Neuroticism, and Sleep duration. Furthermore, in the outcomes study, genetic liability to major depression exhibited significant correlations with factors explaining the severity of the disorder in terms of the number of episodes, hospitalization history, and social function. Additionally, genetic liability to schizophrenia and ADHD showed significant correlations with disease severity, while the genetic liability for Intelligence, as measured by years of education, correlated with social outcomes and the number of episodes. This thesis contributes to the understanding of bipolar disorder by elucidating the complex interplay between disease trajectories, outcomes, and genomic structure. The findings highlight the importance of considering both clinical and genetic factors in the personalized diagnosis and treatment of bipolar disorder patients.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 4 April 2024
Last Modified: 04 Apr 2024 15:29

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