Storm, Catherine Sofie;
(2022)
Using genetics to understand and develop treatments for Parkinson’s disease.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Genome-wide association studies (GWAS) have successfully identified common variants associated with Parkinson’s disease. This approach can however not reliably pinpoint causal genes nor drug targets. Most GWAS-identified variants are found in non-coding regions, and it is unclear how these exert their effect. Many genes have been proposed to harbour rare variants contributing to disease, but there is a lack of replication studies in large cohorts. In this thesis, I aimed to address these research areas using three approaches. First, I used Mendelian randomization (MR) to predict the efficacy of the anti-diabetic GLP-1 mimetic exenatide as a treatment for Parkinson’s disease. I found that GLP-1 mimetics and DPP4 inhibitors (which increase GLP-1 bioavailability) may be protective against Parkinson’s disease, though independently of the GLP-1 receptor in blood. Second, I broadened my approach by applying MR to the druggable genome. I have proposed 23 drug-targeting mechanisms with genetic support for Parkinson’s disease, of which I nominate six as having the strongest MR evidence. Third, I sought to identify whether Parkinson’s-disease-relevant genetic loci make physical contacts with distant DNA. I conducted a Hi-C experiment to create a three-dimensional map of the genome in stem-cell-derived midbrain dopaminergic neurons. My preliminary findings suggest that GWAS loci make significant contacts and that chromatin architecture at the SNCA locus may be altered in patients with an SNCA triplication. These data require further analysis and validation before conclusions can be drawn with confidence.Fourth, I used whole-genome sequencing data to show that rare variants in the NR4A2 gene are unlikely to contribute to Parkinson’s disease risk. This study reinforces the importance of replication and thorough quality control of large-scale genetic sequencing data. Overall, this thesis provides valuable evidence concerning genetically-supported drug targets, long-range DNA-to-DNA contacts made by risk loci, and rare variants in Parkinson’s disease.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Using genetics to understand and develop treatments for Parkinson’s disease |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10144106 |
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