Abstract
Background: Genome-wide association studies (GWAS) in Europeans have robustly associated 111 loci with atrial fibrillation (AF) and 22 loci with stroke risk. However, the functional consequences of these associations have yet to be elucidated. Therefore, this thesis seeks to identify shared genetic effects between methylomic, transcriptomic and metabolomic traits to help improve our understanding of molecular mechanisms underlying stroke and AF.Methods: To investigate this I developed and applied a multiple trait colocalization pipeline using the Bayesian “moloc” method. Molecular traits were considered to be colocalized with AF or stroke if they had a posterior probability of association (PPA)>80%. In addition, to demonstrate that there was evidence that genetic susceptibility for AF was linked to stroke, a two-sample Mendelian randomization (MR) study was conducted.
Results: In Phase I of the study, 23 AF and 11 stroke loci were found to colocalize between DNA methylation and circulating metabolites within the cis region. In Phase II of the study, eQTL data was integrated on the top findings from Phase I. Multiple CpG sites, gene expression and metabolites (mainly lipids and lipoproteins) were found to colocalize with AF and stroke, suggesting shared regulatory relationships between these intermediate phenotypes. Of the 34 prioritized loci, only the 16q22 region (harbouring the HP and ZFHX3 genes) colocalized with both AF and stroke traits. MR analysis suggested that genetic predisposition to AF increases risk of stroke, although there was some evidence for a reverse MR effect.
Conclusions: This thesis demonstrates the application of multi-omics approach to discover genetic pathways linked to cardiovascular disease, and illustrates complexities around issues involving statistical power, directionalities of molecular effects, and tissue specificity. The moloc pipeline and framework developed could be applied to other diseases in the future and will become increasingly valuable as new molecular datasets are published.
| Date of Award | 22 Mar 2022 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Tom R Gaunt (Supervisor), Josine L Min (Supervisor) & Caroline L Relton (Supervisor) |
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