Discovery of genome-wide SNP associations for lung function

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

Abstract

Chronic obstructive pulmonary disease (COPD) is a debilitating and incurable lung disease that affects 900,000 people in the UK with one person dying from COPD every 20 minutes in England. It is well known that smoking can cause lung disease including COPD. However, not all smokers are equally at risk of developing COPD, and not all people who develop COPD are smokers. Genetics also plays a role in lung function and in our risk of developing lung diseases.
Identifying which genes affect how well our lungs work tells us more about the biology underlying lung health and can lead to development of new treatments for COPD. By studying large groups of individuals, for whom we had both measurements of lung capacity and measurements of how much they vary from each other genetically (genetic variation), we have so far identified 52 regions of our DNA where genetic variation affects lung health. However, we know that there are more regions to be identified, and we need larger and more sophisticated studies to achieve this. Identification of more regions will tell us more about which biological mechanisms are important in lung disease and reveal more about potential approaches to therapy.
The aim of this research project is to discover further regions of the genome associated with lung function using data from more than 600,000 individuals. The approaches used to measure genetic variation have improved rapidly in recent times enabling us to simultaneously analyse more genes and other regions of DNA than in previous studies. Combining this with very large sample sizes will enable us to increase the number of regions identified.
Achievement of this aim will tell us more about lung health and disease and could lead to new drugs and treatment which improve the lives of individuals with COPD, or prevent COPD from developing.

Technical Summary

Large GWAS, and analysis of lung function in the extremes of UK Biobank, have brought the total number of lung function associated loci to 52, of which a growing number show association with COPD risk. Larger sample sizes and more sophisticated approaches to variant measurement and imputation are needed to identify additional genetic loci, especially for low frequency and rare variants which might have individually larger effects than common variants. We will utilise sample sizes of up to 600,000 research participants with lung function data through consortium collaborations and UK Biobank, in conjunction with new array designs and larger imputation reference panels to achieve this. We had a lead role in the design of the Affymetrix UK Biobank array through our MRC-funded UK BiLEVE project. Key features of the array include: i) selection of tag variants to optimise imputation of low-frequency variants; ii) improved "exome chip" content based on larger sequencing resources than previous arrays; and iii) custom content designed to maximise coverage of candidate respiratory regions. We have established expertise and pipelines in the analysis of this array which has been shared with additional studies, including the China Kadoorie Biobank, enabling a trans-ethnic meta-analysis of lung function. These studies will not only contribute to fine mapping of signals but, crucially, will provide the substantial number of loci required to more completely undertake pathway analyses and enable scientists worldwide to evaluate the functional importance of these signals.

Planned Impact

The research proposed aims to inform new approaches to prevention and treatment of COPD, and potentially identify subgroups of patients in which particular preventive and treatment strategies might be most effective (stratified medicine). In the UK, 900,000 patients live with COPD, although it is significantly underdiagnosed. The annual direct NHS cost of COPD is around £800m, and an estimated £3.8 billion is lost each year through reduced productivity due to COPD. Furthermore, COPD is the second commonest cause of emergency admissions to hospital and accounts for approximately 30,000 deaths per year. Cigarette smoking is the most well-established lifestyle risk factor for COPD, but not all smokers develop COPD. Smoking is an important risk factor for circulatory and respiratory conditions, cancers and other diseases, accounting for ~463,000 hospital admissions and 79,000 deaths (18% of all deaths) in England annually. Approximately 19% of adults are current smokers, and whilst over £135m is spent in England annually on NHS Stop Smoking Services and smoking cessation pharmacotherapies combined, cessation rates remain disappointing. Improved prevention and treatment of COPD and prevention of other smoking-related diseases could have a substantial health and economic impact.

The 3 NIHR Biomedical Research Units (BRUs) in Leicester and the Collaboration for Leadership in Applied Health Research and Care (CLAHRC) East Midlands, which work closely together, provide appropriate routes to ensure translation of new preventive and treatment advances into health care (in terms of policy and adoption in practice) and provide routes for effective engagement with industry and the NHS. The Department for Health Sciences and Respiratory BRU provide expertise in development of complex interventions, running successful trials (e.g. Brightling is coordinator for two Phase 3 trials), approaches to optimally implement trial evidence in "real-world" settings (with CLAHRC), and to evaluate the effectiveness of systematic approaches for patient safety (e.g. LIIPS - Leicestershire Improvement Innovation and Patient Safety Unit).

Tobin and Wain have a track record of collaborations with industry to advance therapeutic target validation for COPD, including a second collaboration with Pfizer following a productive collaboration established in 2010. Brightling, Siddiqui, Wardlaw and Bradding (NIHR Leicester Respiratory BRU) have collaborations with large and small companies including AZ/MedImmune, GSK, Novartis, Merck, Chiesi, Genentech, NAPP and several biotech and devices companies, including both focused studies and major strategic public/private partnerships such as the MRC/ABPI initiative COPDMAP (lead Brightling). The University of Leicester (including Tobin and Brightling) has been actively involved in discussions with the Precision Medicine Catapult lead and is set to contribute actively, and should benefit from links to, the PMC when it is established, to facilitate rapid translation of advances to clinical and economic benefit. Tobin, Wain and/or Brightling have been actively involved with SMEs through major international initiatives such as AirPROM and local engagement focused on genetic epidemiology projects. Discussions with other SMEs are taking place following our participation at Innovate UK Knowledge Transfer Network activities.

As we have done in recent years, we will make genome-wide results publicly available for the benefit of the scientific community. We will also ensure that the benefits of the data we generate can be realised by other biomedical scientists researching a wide range of disease areas, as we did with the UK BiLEVE project, in which we deposited UK Biobank genome-wide data on the first 50,000 participants to be studied in this way. We will also share our expertise with other established investigators and with basic and clinical scientists in training.

Publications

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Aschard H (2017) Evidence for large-scale gene-by-smoking interaction effects on pulmonary function. in International journal of epidemiology

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Gill D (2017) Age at menarche and lung function: a Mendelian randomization study. in European journal of epidemiology

 
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
 
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 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