Abstract
In this project we 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.
Recent genome-wide association studies (GWAS) have shown genetic variants in 26 regions of the genome associated with lung function (2-5), 7 of which have been so far shown to be associated with COPD . The proportion of the variance in lung function accounted for by these common genetic variants (MAF >5%) remains however modest (~7.5% for FEV1/FVC after accounting for putative undiscovered common variants of similar effect size) . A more complete picture of genetic determinants will emerge when we also understand rarer genetic variants that affect risk of COPD. Identifying such variants could be very important for the next steps in new drug discovery and testing, because genetic variants that are less common in the population tend to have much larger effects.
The common variants associated with lung function to date have similar effect sizes in smokers as in non-smokers, but it is too early to say whether the same will be true for rare variants. As a corollary, understanding why the lung function of some smokers appears to be well-preserved could provide insight into the mechanisms which also affect susceptibility to tobacco smoke. Furthermore, a sizeable proportion of older patients with fixed airflow obstruction have had little or no exposure to tobacco smoke, but the causal mechanisms of their disease and the extent to which these mechanisms overlap with COPD in smokers are poorly understood.
To address these issues we propose a study which would leverage the power of UK Biobank and which will harness the resources and experience of an expert group of UK investigators in respiratory genomics to advance understanding of these phenotypes.