Henry Asrikin, Albert;
(2023)
Understanding Heart Failure Using Human Genetics.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Heart failure (HF) describes the clinical syndrome of fluid congestion that results from structural or electromechanical dysfunction of the heart. HF represents the most rapidly growing cardiovascular condition, affecting more than 64 million people worldwide. Owing to complex interplay between multiple aetiologies and risk factors, identification of causal factors and therapeutic targets across HF subtypes remains challenging. This thesis aims to investigate the causal biology of HF and to identify potential therapeutic targets using human genetics. Towards this aim, first, I developed a multi-modal phenotyping algorithm to define HF subtypes and evaluated their phenotypic characteristics in the UK Biobank cohort. The algorithm was then used to perform a large-scale, multi-centre, multi-ancestry meta-analysis of genome-wide association studies (GWAS) comprising 1.9 million individuals with more than 140,000 HF cases. Leveraging the GWAS results, I identified novel HF genomic loci and characterised the genetic architecture of HF. Next, I performed a functional genomic analysis to characterise HF genomic loci and to prioritise effector tissues, cell types, genes, and causal variants for HF. Further, I conducted a systematic genetic appraisal of the causal associations of common comorbidities, risk factors and cardiac morphofunctional traits across HF subtypes. Finally, I integrated the genomic analysis of HF with population-scale proteomic data to identify and prioritise potential therapeutic targets for HF. In summary, this thesis covers a comprehensive genetic analysis across HF subtypes to advance our understanding of the causal biology of HF and to inform the development of new potential therapeutic strategies.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Understanding Heart Failure Using Human Genetics |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. 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. |
| Keywords: | cardiovascular disease, genetics, heart failure, human genetics |
| UCL classification: | 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 Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10173310 |
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