A program of research in respiratory and cardiovascular genetic epidemiology

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

Abstract

Chronic obstructive pulmonary disease and high blood pressure affect a high proportion of adults in the UK. This program, involving collaborators from several UK and international centres, aims to identify the genetic causes of these disorders. By comparing measures of lung function in tens of thousands of individual study participants for variants at each of millions of different sites across the human genome, we can identify variants associated with lung disease. We will study the impact of these variants in more detail, examining their effect on lung growth, on decline in lung function with age or with disease, on effects of smoking and on response to treatment. Similar discovery and follow-up studies will be undertaken for blood pressure. We can also use the identified genetic variants to tell us more about modifiable non-genetic influences on disease, such as whether dietary deficiency in folate causes high blood pressure. In most cases, we do not expect these variants to accurately predict an individual‘s risk of developing disease, but we do expect the genes identified to give important clues about how the diseases are caused and advance our understanding of how they might be more effectively prevented and treated.

Technical Summary

Aims
(1) To identify sequence and structural variants in the human genome associated with respiratory function and chronic obstructive pulmonary disease
(2) To identify human genomic variants associated with blood pressure and related cardiovascular traits.

Main objectives
1.1. To discover common single nucleotide polymorphisms (SNPs) associated with pulmonary function
1.2. To identify rare SNPs associated with COPD and pulmonary function in existing data and from resequencing novel loci.
1.3. To study common and rare copy number variants (CNVs) associated with pulmonary function.
1.4. To assess the role of genomic variants from 1.1 to 1.3 in: development in pulmonary function, decline in pulmonary function; pulmonary function in diseased individuals; airway response to beta-2 agonists, effect modification of tobacco smoking; Mendelian randomization studies aimed at understanding potentially modifiable intermediate pathways underlying lung function.
2.1. To discover common single nucleotide polymorphisms (SNPs) associated with blood pressure.
2.2. To study common and rare copy number variants (CNVs) associated with blood pressure.
2.3. To assess the role of blood pressure associated variants from 2.1 and 2.2 in: longitudinal change in blood pressure; circadian variation in ambulatory BP; Mendelian randomization studies to assess causal pathways influencing blood pressure. Mendelian randomization studies will utilise variants from 1.1 to 1.3 to investigate the causal mechanisms for the reported association between lung function and cardiovascular disease.
Design and methodology
The research will utilise existing genome-wide association study (GWAS) data in very large sample sizes and will utilise new publicly available data to impute untyped variants (1.1, 2.1). I will employ novel statistical approaches for the detection of rare variant associations (1.2) and deep resequencing (1.2) for regions identified from GWAS. I will further develop methods to study CNVs genome-wide and apply these to large study populations to test CNV associations in 1.3 and 2.2. Causal pathways underlying these traits will be investigated (1.4, 2.3) using carefully phenotyped populations, longitudinal analyses employing generalised linear mixed models we have previously developed, and Mendelian randomization analyses in very large populations using methods we have developed in the group.
Scientific and medical opportunities
Well-designed, adequately powered and carefully analysed genetic association studies can inform understanding of the aetiological pathways underlying disease causation and progression, and may highlight potential targets for prevention and treatment. Disease-associated genetic variants can also be used in traditional epidemiological studies (Mendelian randomization) to inform understanding of intermediate pathways that may be amenable to public health intervention.

Publications

10 25 50
 
Description Citations in clinical reviews - lung function and COPD on future clinical practice
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical reviews
 
Description Collaborative Award in Science & Engineering PhD studentship
Amount £80,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2016 
End 09/2020
 
Description Investigator Award
Amount £1,318,502 (GBP)
Funding ID 202849/Z/16/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2017 
End 12/2021
 
Description Project Grant
Amount £375,835 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2016 
End 03/2018
 
Title Analysis of blood pressure data in epidemiology studies 
Description Methods to deal with data in epidemiology studies in which a proportion of subjects receive antihypertensive treatment 
Type Of Material Improvements to research infrastructure 
Year Produced 2011 
Provided To Others? Yes  
Impact Not yet noticeable (but our 2005 paper on this topic was widely cited and influenced statistical analysis approaches adopted in this field). 
 
Title SpiroMeta consortium 
Description Consortium of cohort studies with spirometry lung function measure and genome-wide association as a resource to study genomics of lung function. 
Type Of Material Improvements to research infrastructure 
Year Produced 2009 
Provided To Others? Yes  
Impact Sharing resources within the consortium. Top 3000 associations made available in late 2009. In 2011 custom chip content (up to 3000 SNPs) has been developed as a resource to other investigators studying resoiratory genetics. 
 
Title GWAS results Feb 2017 
Description Full genome-wide association results for research reported in our Nature Genetics paper published Feb 2017 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact Groups have already contacted us or UK Biobank to access these data. Results available via UK Biobank 
 
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 Press release UK BiLEVE study 
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 o Monday 28th September 2015: MRC press release: "Smokers who survive their habit into old age may hold the key to better lung health for all, according to a study funded by the Medical Research Council"
? Findings of the UK BiLEVE, the first genetic study in UK Biobank led to media reporting (TV, radio, print media) across the world including USA, Australia, South East Asia and BBC World Service programmes timed to reach African and Asian and worldwide audiences.
Year(s) Of Engagement Activity 2015
 
Description Press release, media interviews Nature Genetics paper 
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 release accompanying our Nature Genetics paper Feb 2017 describing novel findings in understanding COPD genetics, including interface of genetic and smoking risks. Link below (Altmetrics) provides a link to press articles, also did radio and TV interviews
Year(s) Of Engagement Activity 2017
URL http://www.nature.com/ng/journal/v49/n3/ng.3787/metrics
 
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 Media (as a channel to the public)
Results and Impact for discovery of loci for pulse pressure and Mean arterial pressure (Sept 2011) and lung function (Sept 2011)

Press coverage of both research outputs
Year(s) Of Engagement Activity 2011
 
Description Royal Society Summer Science Exhibition, July 2012 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact This highly interactive exhibit (http://sse.royalsociety.org/2012/exhibits ) was visited by ~12,000 members of the public (including school children and sixth form students) and ~50,000 visitors were expected to access the online content, where we hosted a virtual exhibit (http://breathless.le.ac.uk/). Only 21 exhibits were chosen from all areas of science in the UK and only four, including our exhibit, were selected for an advance press conference.

This led to coverage in the print media and university website. The BBC World service featured our research and exhibit on the programme "Health Check" on 4th July 2012 http://www.bbc.co.uk/programmes/p00tt7kh). During the two VIP Soirees of the exhibition, our exhibit was attended by policy makers from the health sector, government, funding bodies, the media and industry, including a senior representative of Pfizer, with whom we have an established collaboration.
Year(s) Of Engagement Activity 2012