- Title
- Investigation of clinically actionable components of genomic risk for complex disorders
- Creator
- Reay, William Robert
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2022
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Complex disorders constitute the largest burden on the health care system and include diverse phenotypes such as cancer, cardiovascular and metabolic disease, inflammatory disorders, and mental illness. These complex traits arise from a multifaceted interplay between genetic and environmental factors, with their genetic architecture encompassing a polygenic effect of many heterogenous types of variation spread throughout the genome. Importantly, each individual with any given complex phenotype will possess a unique profile of risk variants, highlighting the biological complexity inherent to these traits. Recent advances in genome-wide association studies (GWAS) have provided unprecedented insights into specific genetic loci associated with complex traits, as well as highlighting widespread genetic overlap between different disorders. Findings from GWAS have the potential to rapidly alter clinical practice as understanding the heritable components of complex disorders may reveal novel drug targets or repurposing opportunities. Moreover, GWAS of environmentally plastic exposures, such as circulating metabolites, could also facilitate insights into factors that could be clinically modulated through analysing their genetic relationship with disease phenotypes. The therapeutic potential of GWAS were therefore investigated through analysis of population level data and a novel framework to aid precision medicine for individuals. Firstly, the pharmagenic enrichment score (PES) method was developed to more specifically target drug repurposing opportunities to individuals for any clinically relevant complex phenotype based on genetic risk annotated to particular druggable pathways, rather than genome wide. The PES approach was demonstrated to provide unique biological insights relative to a genome wide polygenic score. An example of a population-based approach was then applied to uncover genetic evidence to support dietary or pharmacological intervention in regard to glycaemic biology in psychiatry, given dysglycaemia has long been speculated to play a role in mental illness. Data from Mendelian randomisation suggested that elevated circulating fasting insulin may have a protective effect on anorexia nervosa, in line with the known biology associated with insulin signalling. Finally, the two aforementioned approaches were integrated to prioritise drugs that could be repurposed to improve lung function and reduce the risk of pneumonia. Taken together, these data support the clinical value of GWAS and demonstrate multiple lines of genetic evidence could be triangulated to improve clinical practice.
- Subject
- genetics; statistical genetics; genetic epidemiology; functional genomics; precision medicine; drug repurposing
- Identifier
- http://hdl.handle.net/1959.13/1508285
- Identifier
- uon:56115
- Rights
- Copyright 2022 William Robert Reay
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
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| View Details Download | ATTACHMENT01 | Thesis | 14 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 177 KB | Adobe Acrobat PDF | View Details Download |