- Title
- Nucleic acid biomarkers of neurological disorders from brain-derived serum extracellular vesicles
- Creator
- Barnett, Michelle Mia
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2024
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- The global burden of mental health disorders is increasing and a proportion of patients do not respond adequately to available treatments, leading to additional periods of disability and increased mortality. Incomplete knowledge of aetology and limitations of current symptom-based diagnoses have hampered efforts to identify underlying biological mechanisms. Psychiatric disorders arise from both environmental factors and genetic risk leading to dispersed systems level alterations in the brain. The formation and function of brain circuits are controlled at many levels, including posttranscriptional regulation of gene expression. In this context, miRNA are key molecules as they are enriched in brain, display temporal and spatial patterns of abundance and regulate the expression of many genes, including those implicated in psychiatric disorders. Indeed, post-mortem alterations in miRNA, and miRNA biogenesis, have been observed in psychiatric disorders, including schizophrenia. Therefore, these molecules have the potential to refine our understanding of neurobiological mechanisms altered in psychiatry and function as molecular biomarkers. Given that the living human brain is largely inaccessible for molecular studies, novel techniques that allow large scale sampling of brain miRNA from living subjects are needed for biomarker development. Circulating miRNA arise from most human tissues, including the brain, and a proportion are encapsulated in extracellular vesicles (EVs). In addition to protecting their miRNA cargo from degradation, EVs also bear markers of their tissue of origin. This suggests that circulating EVs and their encapsulated miRNA can be enriched on the basis their tissue of origin, thereby providing a miRNA profile from that tissue. To investigate the potential applications for biomarker development, we sequenced small RNA from serum EVs enriched for neuronal origin from a large number of individuals, including subjects with a lifetime diagnosis of schizophrenia. We employed a variety of methods to interrogate this wealth of data, which included clinical and genetic information. We began our analyses by investigating if a psychiatric signature could be detected and demonstrated schizophrenia associated alterations in neuronal origin miRNA expression. We further demonstrated that clinically important subtypes of schizophrenia have profoundly altered miRNA expression and discussed the potential clinical utility of these findings. We then asked if miRNA expression could be leveraged to classify subjects on a neurobiological basis. We investigated this opportunity by utilising machine learning. These powerful analytical tools are capable of assigning class labels for individuals given a large number of variables, which may have classification potential and unspecified relationships between them. We trained and tested various models for differentiating individual schizophrenia subjects from non-psychiatric comparison subjects, to achieve classifier performance approaching clinical utility. From these models we derived compact sets of miRNA that were important to classification and identified their functional implications in pathways that represent plausible biology and novel insights. Given the heritable and complex genetic architecture of schizophrenia, we extended our models by integrating genetic scores that capture common variant contributions to complex traits. We observed increased power to correctly classify subjects and noted that genetic and transcriptional variables are orthogonally informative in this task. Taken together, this project demonstrates circulating miRNA from neuronal origin EVs have application for the development of schizophrenia biomarkers, providing a neurobiological refinement of diagnosis, prognosis and treatment selection.
- Subject
- miRNA; biomarkers; brain; extracellular vesicles; schizophrenia
- Identifier
- http://hdl.handle.net/1959.13/1513313
- Identifier
- uon:56709
- Rights
- This thesis is currently under embargo and will be available from 23.10.2025. Copyright 2024 Michelle Mia Barnett
- Language
- eng
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