Almramhi, Mona Mohammad;
(2023)
Using Genetic Approach to Investigate the Causal Relationship between Environmental Risk Factors and Multiple Sclerosis.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Over the past few years, the study of genetics has been revolutionised by rapid progress in genomewide association studies (GWAS), leading to the uncovering of a large proportion of genetic variants associated with biomarkers, lifestyle factors and disease incidence. However, understanding how these variants mechanistically influence disease phenotypes and/or translating GWAS findings into drug targets have proved challenging. The challenges facing epidemiological studies in distinguishing between causation and association have drawn much interest to the Mendelian randomisation (MR) approach. MR can be viewed as a platform to integrate novel genetic information generated in GWAS or molecular studies (QTL) to inform about causal associations between an exposure and a disease outcome; the demonstrated causal association is less likely to be affected by confounding or reverse causation. This advancement led me to apply the MR approach to uncover the causal link between several environmentally modifiable exposures and the risk of developing multiple sclerosis (MS), as well as the severity of MS. Additionally, I broadened our approach by applying MR to the druggable genome to identify and prioritise new drug targets for MS. Overall, I found genetic evidence that high-density lipoprotein and a range of features linked to obesity (body mass index, weight, fat mass and fat percentage) and stroke, are risk factors for MS development. Additionally, I found genetic evidence supports the casual role of obesity in worsening MS severity. Most importantly, this thesis prioritises several genes (RAC2, CCR4, SLAMF7 and SIK3) with the potential to serve as druggable genes in MS. This finding offers a platform for informing the design of MS preventive strategies.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Using Genetic Approach to Investigate the Causal Relationship between Environmental Risk Factors and Multiple Sclerosis |
| 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 UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences 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 |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10162896 |
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