@article{953831fa616e43349feeec4f5e7a4a58,
title = "Genome-wide association study of chronic sputum production implicates loci involved in mucus production and infection",
abstract = "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. GWASs of respiratory traits were interrogated to identify whether the signals were driven by existing respiratory disease among the cases and variants were further investigated for wider pleiotropic effects using phenome-wide association studies (PheWASs).Results: From a GWAS of 9714 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 FUT2 locus. The four common variant associations were supported by independent studies with a combined sample size of up to 2203 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 including blood cell traits, liver biomarkers, infections, gastrointestinal and thyroid-associated diseases, and respiratory disease.Conclusions: Novel signals at the FUT2 and mucin loci suggest that mucin fucosylation may be 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.",
author = "Packer, {Richard J.} and Nick Shrine and Robert Hall and Melbourne, {Carl A.} and Rebecca Thompson and Williams, {Alex T.} and Paynton, {Megan L.} and Guyatt, {Anna L.} and Allen, {Richard J.} and Lee, {Paul H.} and Catherine John and Archie Campbell and Caroline Hayward and {de Vries}, Maaike and Vonk, {Judith M.} and Jonathan Davitte and Edith Hessel and David Michalovich and Betts, {Joanna C.} and Ian Sayers and Astrid Yeo and Hall, {Ian P.} and Tobin, {Martin D.} and Wain, {Louise V.}",
note = "Funding Information: Support statement: L.V. Wain holds a GSK/Asthma and Lung UK Chair in Respiratory Research (C17-1). M.D. Tobin is supported by a Wellcome Trust Investigator Award (WT202849/Z/16/Z). M.D. Tobin and I.P. Hall hold NIHR Senior Investigator Awards. C. John held a Medical Research Council Clinical Research Training Fellowship (MR/P00167X/1). L.V. Wain, M.D. Tobin, I. Sayers and I.P. Hall report collaborative research funding from GSK to undertake the submitted work. The research was partially supported by the NIHR Leicester Biomedical Research Centre and the NIHR Nottingham Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. This research was funded in part by the Wellcome Trust. We acknowledge the support of the Health Data Research UK BREATHE Digital Innovation Hub (UKRI Award MC_PC_19004). This research was conducted under UK Biobank application 45243. This research used the SPECTRE and ALICE High Performance Computing Facility at the University of Leicester. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006) and is currently supported by the Wellcome Trust (216767/Z/19/Z). Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) Reference 104036/Z/14/Z). C. Hayward is supported by a Medical Research Council University Unit Programme grant MC_UU_00007/10 (QTL in Health and Disease). Recruitment to the Generation Scotland CovidLife study was facilitated by SHARE (Scottish Health Research Register and Biobank). SHARE is supported by NHS Research Scotland, the Universities of Scotland and the Chief Scientist Office of the Scottish Government. Funding information for this article has been deposited with the Crossref Funder Registry. Funding Information: L.V. Wain holds a GSK/Asthma and Lung UK Chair in Respiratory Research (C17-1). M.D. Tobin is supported by a Wellcome Trust Investigator Award (WT202849/Z/16/Z). M.D. Tobin and I.P. Hall hold NIHR Senior Investigator Awards. C. John held a Medical Research Council Clinical Research Training Fellowship (MR/P00167X/1). L.V. Wain, M.D. Tobin, I. Sayers and I.P. Hall report collaborative research funding from GSK to undertake the submitted work. The research was partially supported by the NIHR Leicester Biomedical Research Centre and the NIHR Nottingham Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. This research was funded in part by the Wellcome Trust. We acknowledge the support of the Health Data Research UK BREATHE Digital Innovation Hub (UKRI Award MC_PC_19004). This research was conducted under UK Biobank application 45243. This research used the SPECTRE and ALICE High Performance Computing Facility at the University of Leicester. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006) and is currently supported by the Wellcome Trust (216767/Z/19/Z). Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) Reference 104036/Z/14/Z). C. Hayward is supported by a Medical Research Council University Unit Programme grant MC_UU_00007/10 (QTL in Health and Disease). Recruitment to the Generation Scotland CovidLife study was facilitated by SHARE (Scottish Health Research Register and Biobank). SHARE is supported by NHS Research Scotland, the Universities of Scotland and the Chief Scientist Office of the Scottish Government. Funding information for this article has been deposited with the Crossref Funder Registry. Publisher Copyright: Copyright {\textcopyright} The authors 2023.",
year = "2023",
month = jun,
day = "1",
doi = "10.1183/13993003.01667-2022",
language = "English",
volume = "61",
journal = "European Respiratory Journal",
issn = "0903-1936",
publisher = "EUROPEAN RESPIRATORY SOC JOURNALS LTD",
number = "6",
}