Genome-wide association study of chronic sputum production implicates loci involved in mucus production and infection

Background Chronic sputum production impacts on quality of life and is a feature of many respiratory diseases. Identification of the genetic variants associated with chronic sputum production in a disease agnostic sample could improve understanding of its causes and identify new molecular targets for treatment. Methods We conducted a genome-wide association study (GWAS) of chronic sputum production in UK Biobank. Signals meeting genome-wide significance (P<5×10−8) were investigated in additional independent studies, were fine-mapped, and putative causal genes identified by gene expression analysis. GWAS of respiratory traits were interrogated to identify whether the signals were driven by existing respiratory disease amongst the cases and variants were further investigated for wider pleiotropic effects using phenome-wide association studies (PheWAS). Findings From a GWAS of 9,714 cases and 48,471 controls, we identified six novel genome-wide significant signals for chronic sputum production including signals in the Human Leukocyte Antigen (HLA) locus, chromosome 11 mucin locus (containing MUC2, MUC5AC and MUC5B ) and the FUT2 locus. The four common variant associations were supported by independent studies with a combined sample size of up to 2,203 cases and 17,627 controls. The mucin locus signal had previously been reported for association with moderate-to-severe asthma. The HLA signal was fine-mapped to an amino-acid change of threonine to arginine (frequency 36.8%) in HLA-DRB1 (HLA- DRB1 *03:147). The signal near FUT2 was associated with expression of several genes including FUT2 , for which the direction of effect was tissue dependent. Our PheWAS identified a wide range of associations. Interpretation Novel signals at the FUT2 and mucin loci highlight mucin fucosylation as a driver of chronic sputum production even in the absence of diagnosed respiratory disease and provide genetic support for this pathway as a target for therapeutic intervention. ### Competing Interest Statement Conflicts of interest L.V.W. holds a GSK / Asthma + Lung UK Chair in Respiratory Research (C17-1). M.D.T. is supported by a Wellcome Trust Investigator Award (WT202849/Z/16/Z). M.D.T. and I.P.H. hold NIHR Senior Investigator Awards. C.J. held a Medical Research Council Clinical Research Training Fellowship (MR/P00167X/1). LVW, MDT, IS and IPH report collaborative research funding from GSK to undertake the submitted work. ### Funding Statement L.V.W. holds a GSK / Asthma + Lung UK Chair in Respiratory Research (C17-1). M.D.T. is supported by a Wellcome Trust Investigator Award (WT202849/Z/16/Z). M.D.T. and I.P.H. hold NIHR Senior Investigator Awards. C.J. held a Medical Research Council Clinical Research Training Fellowship (MR/P00167X/1). LVW, MDT, IS and IPH report collaborative research funding from GSK to undertake the submitted work. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Data is from the UK Biobank study. more information on gaining access to the data can be found here: I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Genome-wide association statistics from the case-control analysis of chronic sputum production will be made available via GWAS Catalog [to be submitted following peer-review].