- Title
- Exploring causal architecture of schizophrenia and Alzheimer's disease to identify new drug targets
- Creator
- Maserrat, Shahin
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2024
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Schizophrenia and Alzheimer's disease contribute significantly to the global burden of disease. Although distinct in terms of their clinical presentation and progression, they are both common chronic complex diseases affecting the central nervous system. While these conditions are typically associated with significant cognitive impairment and a decline overall mental health they also have distinct clinical profiles. While these conditions arise from complex interactions between genetic and environmental factors, there is growing evidence suggesting there may be overlapping genetic risk factors and molecular pathways between the two conditions. Both conditions involve in synaptic function and immune dysfunction with research showing that individuals with schizophrenia are at an increased risk of developing Alzheimer's Disease later in life. In the case of schizophrenia, it is widely accepted that multiple genes contribute to the risk of developing the disorder. However, the genetic architecture is complex and includes both common genetic variants with small effects and rare genetic variants with larger effects. Environmental factors, such as prenatal infections, complications during birth, and psychosocial stress, also contribute to the risk for the disorder. Similarly, the complete genetic landscape of Alzheimer's is also complex and multifactorial with many genetic factors, including variations in genes involved in beta-amyloid metabolism, tau protein regulation, and immune response, are associated with the risk and progression of the Disease. Genome-wide association studies (GWAS) have emerged as a valuable approach providing remarkable insights into the genetic underpinnings of complex disorders, including neurodegenerative and psychiatric conditions. While GWAS has been successful in identifying associations between genetic variants, such as single nucleotide polymorphisms (SNPs), it does not typically pinpoint the causal genes and SNPs responsible for the observed associations. To gain a more comprehensive understanding we need to narrow down our focus and conduct further investigations to identify potential drug targets. Follow-up studies, such as fine-mapping and functional analyses, are necessary to ascertain the causal genes and their specific variants. These deeper analyses help us unravel the biological mechanisms underlying the disorders and identify precise genetic targets for therapeutic intervention. In this thesis, my primary focus was investigating the causal components of schizophrenia and Alzheimer's Disease. To achieve this, I employed an integrative analysis approach to reveal the most functionally relevant genes and single SNPs associated with schizophrenia. This involved integrating data from diverse sources, including GWAS, gene expression studies, and functional annotations. I also employed various biological approaches to validate the findings. By optimizing experimental techniques and utilizing relevant cell models, we sought to confirm the functional significance of the associated genes and SNPs. Furthermore, my investigations exploited systems biology to identify potential drug targets for Alzheimer's Disease. This identified specific genes and proteins that could serve as promising targets for therapeutic intervention. These targets hold the potential using precision medicine to modulate disease progression and alleviate symptoms associated with Alzheimer's Disease. In this approach the best treatment options for individual patients are determined by leveraging pharmagenic enrichment score (PES). In this approach we aimed to optimize treatment selection, tailoring drug choices based on an individual's specific genetic makeup. Overall, this thesis contributes to the field by providing a comprehensive list of promising genes and potential drug targets associated with schizophrenia and Alzheimer's Disease.
- Subject
- schizophrenia; Alzheimer's disease; precision medicine; drug targets
- Identifier
- http://hdl.handle.net/1959.13/1506667
- Identifier
- uon:55915
- Rights
- This thesis is currently under embargo and will be available from 22.05.2024, Copyright 2024 Shahin Maserrat
- Language
- eng
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