Approved research

Replication of genetic variant associations with cardiovascular disease and its risk factors

Lay summary

Cardiovascular disease (CVD) is attributable to a combination of genetic and non-genetic risk factors. These risk factors include elevated blood pressure, cholesterol, smoking and obesity that are themselves known to have a heritable component. The aim of this project is to evaluate findings from genetic association studies (from bespoke genotyping array experiments) of CVD and related risk factors. In addition, through meta-analyses with existing datasets, we aim to discover new loci associated with these traits. This proposal will confirm or refute previous genetic risk loci and lead to the identification of novel genetic associations with CVD and its risk factors. A part of this proposal will focus on replication of associations of low-frequency and rare variants, therefore the proposed research project has great potential to identify causal variants and genes [PMID:19264985]. Our results could lead to the identification of potential new drug targets, such as the previously identified PCSK9 gene that is currently in phase 2 trials [PMID:25440796] as a target to reduce LDL cholesterol and improve CVD events. We have previously genotyped large numbers of samples with bespoke genotyping arrays. This identified putative novel regions of the genome associated with CVD and its risk factors. However, to have true confidence in these associations they have to be reproduced in independent samples. To enable this replication, genetic analysis of coronary heart disease, stroke and their risk factors will be performed in the UK Biobank samples by fitting appropriate statistical models. Furthermore, a meta-analysis will be performed combining UK Biobank association results with the existing results to identify additional novel associations. To maximise statistical power the full cohort of 500,000 individuals will be required.

Cardiovascular disease (CVD) is attributable to a combination of genetic and non-genetic risk factors. These risk factors include elevated blood pressure, cholesterol, smoking and obesity that are themselves known to have a heritable component. The aim of this project is to evaluate findings from genetic association studies (from bespoke genotyping array experiments) of CVD and related risk factors. In addition, through meta-analyses with existing datasets, we aim to discover new loci associated with these traits.

NEW SCOPE: we wish to extend the scope of this project in several ways:

1) extension from major well-studied CVD outcomes (e.g. MI, stroke) to other less well-studied vascular (e.g. AAA, VTE), metabolic (e.g. metabolites) and renal (e.g. pyelonephritis) outcomes and risk factors;

2) expansion from replication of previous genetic signals using bespoke arrays to include wide-angled genetic discovery using genomewide imputation or sequencing;

3) consideration of multiple genetic variants, rather than just individual variants, such as in aggregated rare variant tests or polygenic risk scores.