Study of common and rare genetic variants in respiratory health: the UK Biobank Lung Exome Evaluation (UK BiLEVE) consoertium

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.

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).