Study of common and rare genetic variants in respiratory health: the UK Biobank Lung Exome Evaluation (UK BiLEVE) consoertium
Lead Research Organisation:
University of Nottingham
Department Name: UNLISTED
Abstract
Lung function is an important indicator of respiratory health and moratlity. Measures of lung function show irreversible airway ostruction in chronic obstructive pulmonary disease (COPD), a progressive condition affecting 900,000 people in the UK. Smoking is a strong risk factor for COPD but not all smokers are equaly susceptible. Genetic approaches to understanding the mechanisms underlying the maintenance of good lung others, aim to reveal previously unknown molecular targets for drug development and to facilitiate stratified approaches to treatment and care. This project aims to detect rare genetic variants associated with lung function. Once discovered, such variants tend to exert a large effect on disease risk and provide a means to translate findings from genetic studies of lung function to clinical relevant research and development. The proposed study leverages the power of Uk Biobank and respiratory genomics to advance understanding of lung function and COPD. This project will use a customised respiratory exome chip in 50,000 UK Biobank participants, selected according to their smoking history and lung function status at baseline. This project therefore requires teh use of data (spirometry, smoking and other lifestyle factors) and DNA samples.
Technical Summary
COPD is a long term progressive condition affecting approximately 900,000 people in the UK which accounts for ~30,000 deaths and more than £500m of NHS costs annually1. Management of patients with COPD includes symptomatic control, smoking cessation support where appropriate, and prevention of exacerbations, but there is no therapy that can reliably alter disease progression. Genetic approaches to understanding the mechanisms underlying COPD development and progression aim to reveal previously unknown molecular targets for drug development and unravel disease heterogeneity to facilitate stratified approaches to treatment and care.
In this project we will identify associations between both rare and common single nucleotide polymorphisms (SNPs) and phenotypes defined by the extremes of the lung function distribution in heavy smokers and in never-smokers in the UK Biobank population (50,000 individuals in total). Specific scientific aims include:
i. To identify rare, putative functional, genetic variants associated with COPD susceptibility in heavy smokers;
ii. To identify rare genetic variants associated with resistance to tobacco smoke (by studying heavy smokers with well-preserved lung function);
iii. To identify rare genetic variants associated with COPD susceptibility among never-smokers;
iv. To identify rare genetic variants associated with high lung function measures among never-smokers;
v. To study association with these phenotypes of common SNPs (minor allele frequency (MAF)>5%) already reported to have shown genome-wide association with lung function;
vi. To study association with these phenotypes in almost 1500 additional independent genomic regions in which suggestive associations with lung function have been shown for common SNPs in genome-wide association studies;
vii. To identify rare genetic variants associated with tobacco addiction;
viii. To examine interactions between smoking exposure and genetic associations with lung function in this population
ix. To undertake preliminary functional work to provide additional biological insights into key associations detected, by profiling gene expression at the mRNA level and, where appropriate, at the protein level.
In addition the project has three more general aims:
x. To provide an extensive publicly available dataset for the international research community describing associations between lung function and both common variants and intermediate/rare frequency SNPs
xi. To provide a DNA resource for UK Biobank which will cover 10% of the UK Biobank population to facilitate further genetic studies of other phenotypes
xii. To serve as an early example of the study of gene-environment (in particular, gene-smoking) interactions, which may inform the study of the joint effects of genetic and environmental factors of other traits (one of the key objectives in establishing UK Biobank).
In this project we will identify associations between both rare and common single nucleotide polymorphisms (SNPs) and phenotypes defined by the extremes of the lung function distribution in heavy smokers and in never-smokers in the UK Biobank population (50,000 individuals in total). Specific scientific aims include:
i. To identify rare, putative functional, genetic variants associated with COPD susceptibility in heavy smokers;
ii. To identify rare genetic variants associated with resistance to tobacco smoke (by studying heavy smokers with well-preserved lung function);
iii. To identify rare genetic variants associated with COPD susceptibility among never-smokers;
iv. To identify rare genetic variants associated with high lung function measures among never-smokers;
v. To study association with these phenotypes of common SNPs (minor allele frequency (MAF)>5%) already reported to have shown genome-wide association with lung function;
vi. To study association with these phenotypes in almost 1500 additional independent genomic regions in which suggestive associations with lung function have been shown for common SNPs in genome-wide association studies;
vii. To identify rare genetic variants associated with tobacco addiction;
viii. To examine interactions between smoking exposure and genetic associations with lung function in this population
ix. To undertake preliminary functional work to provide additional biological insights into key associations detected, by profiling gene expression at the mRNA level and, where appropriate, at the protein level.
In addition the project has three more general aims:
x. To provide an extensive publicly available dataset for the international research community describing associations between lung function and both common variants and intermediate/rare frequency SNPs
xi. To provide a DNA resource for UK Biobank which will cover 10% of the UK Biobank population to facilitate further genetic studies of other phenotypes
xii. To serve as an early example of the study of gene-environment (in particular, gene-smoking) interactions, which may inform the study of the joint effects of genetic and environmental factors of other traits (one of the key objectives in establishing UK Biobank).
People |
ORCID iD |
Ian Hall (Principal Investigator) |
Publications
Jackson VE
(2018)
Meta-analysis of exome array data identifies six novel genetic loci for lung function.
in Wellcome open research
Ketelaar ME
(2021)
Phenotypic and functional translation of IL33 genetics in asthma.
in The Journal of allergy and clinical immunology
Miller S
(2016)
Genes associated with polymorphic variants predicting lung function are differentially expressed during human lung development.
in Respiratory research
Moll M
(2020)
Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts.
in The Lancet. Respiratory medicine
O'Connell J
(2016)
Haplotype estimation for biobank-scale data sets.
in Nature genetics
Obeidat M
(2015)
Molecular mechanisms underlying variations in lung function: a systems genetics analysis.
in The Lancet. Respiratory medicine
Portelli MA
(2020)
Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium.
in JCI insight
Sakornsakolpat P
(2019)
Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.
in Nature genetics
Shrine N
(2019)
Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study.
in The Lancet. Respiratory medicine
Shrine N
(2019)
New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries.
in Nature genetics
Soler Artigas M
(2015)
Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation.
in Nature communications
Wain LV
(2015)
Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank.
in The Lancet. Respiratory medicine
Wain LV
(2015)
Use of FEV1 as a measure of lung health in the UK BiLEVE study - Authors' reply.
in The Lancet. Respiratory medicine
Description | BI research collaboration |
Amount | € 250,000 (EUR) |
Organisation | Boehringer Ingelheim |
Sector | Private |
Country | Germany |
Start | 01/2018 |
End | 12/2018 |
Description | BREATHE HDRUK Digital Innovation Hub |
Amount | £4,700,000 (GBP) |
Organisation | Health Data Research UK |
Sector | Private |
Country | United Kingdom |
Start | 08/2019 |
End | 08/2022 |
Description | Chiesi foundation |
Amount | € 50,000 (EUR) |
Organisation | Chiesi |
Sector | Private |
Country | Italy |
Start | 06/2013 |
End | 07/2014 |
Description | GSK research collaboration |
Amount | £1,000,000 (GBP) |
Organisation | GlaxoSmithKline (GSK) |
Sector | Private |
Country | Global |
Start | 12/2017 |
End | 12/2020 |
Description | Nottingham BRC |
Amount | £23,600,000 (GBP) |
Organisation | National Institute for Health Research |
Department | NIHR Biomedical Research Centre |
Sector | Public |
Country | United Kingdom |
Start | 03/2017 |
End | 03/2022 |
Description | Pfizer internal funds |
Amount | £400,000 (GBP) |
Organisation | Pfizer Inc |
Sector | Private |
Country | United States |
Start | 01/2015 |
End | 12/2016 |
Description | Pfizer internal funds |
Amount | £540,000 (GBP) |
Organisation | Pfizer Ltd |
Sector | Private |
Country | United Kingdom |
Start | 12/2012 |
End | 12/2014 |
Description | industry collaboration, |
Amount | £180,000 (GBP) |
Organisation | Boehringer Ingelheim |
Sector | Private |
Country | Germany |
Start | 11/2016 |
End | 10/2017 |
Title | UK BiLEVE and UK biobank genotyping chips |
Description | genotyping platofrm combining exome and genome wide content for use if UK and Caucasian populations |
Type Of Material | Technology assay or reagent |
Year Produced | 2014 |
Provided To Others? | Yes |
Impact | Genotyping ongoing for several studies with this platform will result in outputs in 2014/15. Contribution to UK Biobank genotyping platform |
Title | GASP database |
Description | Severe asthma genetics study, data submitted to SAIL and included in Gateway project |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | contributed to BREATH DIH |
Title | Genotype data for UK Biobank |
Description | As above: provosion of genotype data on 50,000 individuals in UK biobank |
Type Of Material | Database/Collection of data |
Year Produced | 2014 |
Provided To Others? | Yes |
Impact | Publications in preparation. |
Title | UK biobank analyses |
Description | Additional data delivered to UK Biobank on genetic associations with lung function |
Type Of Material | Database/Collection of data |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | collaborative working with several industry and academic partners |
Description | Ningbo hospitals |
Organisation | Ningbo Number One Hospital |
Country | China |
Sector | Hospitals |
PI Contribution | Provision of laboratory facilities for visiting scholar during 2015 for 12 months to study molecular genetics of lung function associated genes |
Collaborator Contribution | Salary, travel and living costs for visiting fellow |
Impact | formal agreement with Ningbo number 1 hospital and planned additional academic exchanges |
Start Year | 2015 |
Description | Orion Pharma |
Organisation | Orion Corporation |
Department | Orion Diagnostica Ltd |
Country | Finland |
Sector | Private |
PI Contribution | Advice and input on use of genetic/omic/biomarker approaches to target validation |
Collaborator Contribution | Use of UK Biobank and other data sets for analysis |
Impact | Research grant proposed |
Start Year | 2018 |
Description | Media interviews |
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 | Series of interviews following publication of Lancet Resp Med paper on UK biobank, coupled with media releases from MRC and Univeristy of Nottingham. Interviews included multiple local radio stations, Today programme, ABC News 24, San Francisco Bay radio and others |
Year(s) Of Engagement Activity | 2015 |
Description | NG paper 2017 media |
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 | Press release and consequent media interviews including TV and radio interviews |
Year(s) Of Engagement Activity | 2017 |
Description | NIHR Nottingham BRC conference |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | Key note presentation at inaugural NIHR Nottingham BRC conference, associated video interviews and press releases |
Year(s) Of Engagement Activity | 2017 |
Description | Press release, lung function genetics and smoking 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 highlighting use of genetic strategies to address COPD, both in smokers and nonsmokers |
Year(s) Of Engagement Activity | 2019 |
Description | UK biobank regional event |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Talk to UK Biobank regional event for research participants |
Year(s) Of Engagement Activity | 2015 |
Description | radio interview |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Radio interview on collaboration between Nottingham, Leicester and GSK on lung function genetic studies |
Year(s) Of Engagement Activity | 2018 |
Description | uk biobank meeting |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | UK Biobank workshop, Houses of Parliament |
Year(s) Of Engagement Activity | 2017 |
Description | video for UK biobank website |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Youtube video accessed from UK Biobank website publicity for UK biobank resource |
Year(s) Of Engagement Activity | 2013 |