Association of ADRB2 gene variants with lung function and related traits in UK Biobank

<bold>Introduction:</bold> The effect of coding polymorphisms of the beta-2 adrenergic receptor gene (<italic>ADRB2</italic>) on functional properties of the receptor is well-established, yet their association with respiratory traits and response to beta-2 agonists remains controversial. <bold>Methods:</bold> To identify pleiotropic effects of <italic>ADRB2</italic> common and rare coding variants, we performed respiratory-focused and phenome-wide association studies in UK Biobank. <bold>Results:</bold> A robust association between the Thr164Ile variant (rs1800888) and spirometry-based measures of lung function (0.0067 decrease in FEV1/FVC per minor allele, P = 9.1x10-28) was found. Conditional analyses demonstrated that this association was independent of other variants across the gene. Despite previous reports, we found no association between <italic>ADRB2</italic> variants and asthma or asthma exacerbations. Furthermore, there was no evidence for association with asthma exacerbations amongst individuals self-reporting use of long-acting beta-2 agonists. Using the Olink proteomic data in UK Biobank, we were also able to show association between <italic>ADRB2</italic> polymorphisms and 198 proteins (P<0.01), enriched for wound healing, immune-related, and cancer signalling pathways. Discussion: In a comprehensive analysis of coding variation in the <italic>ADRB2</italic> gene and a broad range of respiratory and non-respiratory phenotypes in UK Biobank, we identify associations with lung function traits that are likely driven by the Thr164Ile variant.