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Title: Applications of genetic data to identify cardiovascular disease mechanisms and therapeutic opportunities
Author: Gill, Dipender
ISNI:       0000 0004 9350 9286
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2020
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Recent years have offered a wealth of genetic association data, with a concurrent explosion in the availability of methods for exploring causal effects through randomly allocated genetic variants that serve as proxies for traits of interest. This thesis investigates the state of this field within the remit of cardiovascular disease. Following an introduction into cardiovascular disease and Mendelian randomization (MR), the research focuses on dietary, social and pharmacological exposures as demonstrative examples for highlighting the breadth of techniques that can be harnessed towards understanding underlying mechanisms and therapeutic opportunities. Both two-sample and one-sample MR analyses are performed, using genetic summary data from large-scale consortia and the UK Biobank. Sample sizes for individual analyses typically exceed tens of thousands of participants. A diverse array of MR methods are employed, appropriate to the setting and objective of each analysis. Considering systemic iron status as a diet-related trait, genetic instruments are identified with consequent MR analyses supporting a protective effect on risk of cardiovascular outcomes related to atherosclerosis but a detrimental effect on outcomes related to thrombosis arising from stasis of blood. Phenome-wide association study further highlights effects of systemic iron status outside the remit of cardiovascular disease. In the investigation of social factors, MR mediation analysis techniques are applied to identify the pathways by which education affects cardiovascular disease risk, with multivariable MR further used to disentangle the direct effects of education and intelligence respectively. In the investigation of pharmacological exposures, genetic instruments for antihypertensive drugs are identified and validated by comparing against corresponding estimates from clinical trials. Phenome-wide association study is used to identify possible side-effects and repurposing opportunities, with a potential detrimental effect of calcium channel blockers identified on risk of diverticulosis. The final section provides an overview of the current state of applied MR, as well as future perspectives.
Supervisor: Dehghan, Abbas ; Tzoulaki, Ioanna Sponsor: Imperial College London
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral