A program of research in cardiovascular genetic epidemiology

Lead Research Organisation: University of Leicester
Department Name: Health Sciences

Abstract

High blood pressure affects around 30% of all adults in England. This program, involving researchers from the University of Leicester, and from St. George’s Medical School, aims to identify the genetic causes of high blood pressure. With my collaborators, I will try to identify regions of the human genome and the variants within them that affect blood pressure. We will screen more than half a million points in the genome where key variations occur in 1500 people from the 1958 Birth Cohort. We will build on these findings by studying some genomic regions in detail in the GRAPHIC study, involving 500 Leicestershire families who have had blood pressure measured over a complete 24-hour period. At the same time, I will work with other researchers at the University of Leicester to explore the impact of some common, but poorly-understood, types of structural variation in the human genome. We will also develop powerful new ways of combining all these types of information to identify genes that affect blood pressure. Our aim is to find variations that cause high blood pressure and these findings will improve our understanding of how high blood pressure occurs, and how it can be prevented and treated.

Technical Summary

AIMS
(1) to identify genetic variants associated with blood pressure (BP) and related cardiovascular phenotypes, using genome-wide and candidate region approaches;
(2) to develop new statistical approaches to maximise the power of genetic association studies, by incorporating different classes of phenotypic information and by utilising information on common types of genomic variation, including copy number variation.

MAIN OBJECTIVES
(1.1) to investigate the quantitative effect of candidate gene variants on mean 24h ambulatory BP;
(1.2) to investigate genetic and environmental determinants of circadian variation in 24hour BP;
(1.3) to assess the effect of genetic variants on key ECG phenotypes, including left ventricular mass and QT interval;
(1.4) to study genome-wide association with BP to inform the candidate gene approaches described above;
(2.1) to develop statistical approaches to model circadian variation in BP that utilize all available measures from ambulatory monitoring;
(2.2) to develop analytical methods that combine different classes of phenotypic information (e.g. binary and quantitative) to maximize the power of genetic studies of complex disease;
(2.3) to develop statistical approaches to appropriately model copy number variation, and to assess the implications of this kind of genomic variation on the statistical power of large-scale genetic association studies.

DESIGN AND METHODOLOGY
Objectives 1.1.to 1.3 utilise a funded collection of 2000 intensively-phenotyped individuals from 500 nuclear families representative of the general population. The family-based design ensures robustness to population stratification and permits segregation analysis, providing rational guidance to the future search for BP candidate genes. Our analytical approaches are based on generalized linear mixed models (GLMMs) fitted using Gibbs sampling in WinBUGS; these are suitable for family data, even when a proportion of subjects receive antihypertensives. Objective 1.4 will be achieved using data on 675,000 genomic markers on 1500 subjects in the 1958 Birth Cohort, using adjustments for antihypertensive treatment. I will also extend methods previously developed by our group, including GLMMs and graphical models, to utilize all available phenotypic information (2.1-2.2) and appropriately model common types of genomic variation, particularly copy number variants (2.3).

SCIENTIFIC AND MEDICAL OPPORTUNITIES
With careful study design, adequately sized studies and appropriate analytical approaches, associations between genetic variants and a range of common complex phenotypes, such as BP, will be found and replicated. Genetic associations with BP will inform understanding of the aetiological pathways underlying high BP, thereby informing preventive and treatment strategies that will reduce the risk of stroke, myocardial infarction and other complications of high BP.

Publications

10 25 50
 
Description CRD grant/EMDA
Amount £50,000 (GBP)
Organisation East Midlands Development Agency 
Sector Public
Country United Kingdom
Start 10/2010 
End 03/2011
 
Description Collaborative Project Grant
Amount £563,000 (GBP)
Organisation Pfizer Ltd 
Sector Private
Country United Kingdom
Start 11/2010 
End 11/2012
 
Description Project grant/Medisearch
Amount £14,700 (GBP)
Organisation University of Leicester 
Department Medisearch
Sector Charity/Non Profit
Country United Kingdom
Start 05/2010 
End 04/2013
 
Description Senior Clinical Fellowship
Amount £1,788,159 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2011 
End 12/2015
 
Title Spirometa consortium 
Description New consortium to study genome-wide association with lung function 
Type Of Material Improvements to research infrastructure 
Year Produced 2009 
Provided To Others? Yes  
Impact Discovery of 5 new loci for lung function. The top 2000 loci from this consortium are being made immediately available to other researchers and a larger consortium formed to advance the field. Has formed the basis for an even larger consortium genome-wide association study. 
 
Description Global BPGen Consortium 
Organisation Queen Mary University of London
Department Barts and The London School of Medicine and Dentistry
Country United Kingdom 
Sector Academic/University 
PI Contribution Jointly steered a large consortium discovering eight new loci for blood pressure, steering group member for new discoveries in genetics of systolic and diastolic BP (2011) and led genomic study for pulse pressure in 2011.
Collaborator Contribution Complimentary expertise
Impact Nature Genetics papers (2009,2011) and Nature paper (2011)
Start Year 2007
 
Description SpiroMeta Consortium 
Organisation University of Nottingham
Department School of Molecular Medical Sciences Nottingham
Country United Kingdom 
Sector Academic/University 
PI Contribution I lead the consortium (co-lead Ian Hall), which has strengthened and grown over the last year
Collaborator Contribution Joint leadership of the consortium, complimentary areas of research expertise
Impact 2 Nature Genetics papers (2010, 2011), 1 AJRCCM paper (2011), 1 Plos One article (2011), other outputs in progress
Start Year 2008
 
Description Spirometa-CHARGE consortia collaboration 
Organisation National Institutes of Health (NIH)
Department National Institute of Environmental Health Sciences
Country United States 
Sector Public 
PI Contribution Joint study of genetic determinants of lung function in very large sample sizes. I have led the genome-wide study of main genetic effects and led the follow-up stages of this study.
Collaborator Contribution Contribution of additional cohorts to a collaborative prospective meta-analysis
Impact In progress
Start Year 2009
 
Description Frank May Prize Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact I was awarded the Frank May Prize Medal by the University of Leicester in 2009, in recognition of research excellence. The award holder is required to deliver a public lecture advertised in the local press. This was delivered to a full lecture theatre and was received well. Attendees included sixth-former students from local schools.

Well publicised in local press. I received direct feedback from the sixth-form students and from other attendees.
Year(s) Of Engagement Activity 2009
 
Description Press releases 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Press releases for discovery of loci for blood pressure (May 2009) and lung function (Dec 2009)

Press coverage
Year(s) Of Engagement Activity 2009