Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent patient populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.
Through new detailed quality control and analyses of spirometric measures of lung function in UK Biobank and expansion of the SpiroMeta Consortium, our study entailed a near seven-fold increase in sample size over previous studies of similar ancestry to address the following aims:
(i) to generate a high yield of genetic markers associated with lung function;
(ii) to confirm and fine-map previously reported lung function signals;
(iii) to investigate the putative causal genes and biological pathways through which lung function associated variants act, and their wider pleiotropic effects on other traits; and
(iv) to generate a weighted genetic risk score for lung function and test its association with COPD susceptibility in individuals of European and other ancestries.
Common and rare genetic variants in respiratory health: the UK Biobank Lung Exome Variant Evaluation (UK BiLEVE) consortium
Lung function is an important indicator of respiratory health and mortality. Measures of lung function show irreversible airway obstruction 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 equally susceptible. Genetic approaches to understanding the mechanisms underlying the maintenance of good lung function in some people, and underlying the development of COPD in others, aim to reveal previously unknown molecular targets for drug development and to facilitate stratified approaches to treatment and care. This project aims to detect rare genetic variants associated with lung function. Once discovered, such variants would be very useful tools for the scientific community, because 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 the resources and experience of an expert group of UK collaborators in 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.
Louise V Wain, et al. Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets es and standard errors.
|Lead investigator:||Martin Tobin|
|Lead institution:||University of Leicester|