@article{969e038c468f48e48b82cce3d05d3726,
title = "Genome wide association study of Preserved Ratio Impaired Spirometry (PRISm)",
abstract = "Background: Preserved Ratio Impaired Spirometry (PRISm) is defined as FEV1 <80% predicted, FEV1/FVC ≥0.70. PRISm is associated with respiratory symptoms and co-morbidities. Our objective was to discover novel genetic signals for PRISm and see if they provide insight into the pathogenesis of PRISm and associated co-morbidities.Methods: We undertook a genome-wide association study (GWAS) of PRISm in UK Biobank participants (Stage 1), and selected SNPs reaching genome-wide significance for replication in 13 cohorts (Stage 2). A combined meta-analysis of Stage 1 and Stage 2 was done to determine top SNPs. We used cross-trait Linkage Disequilibrium score regression to estimate genome-wide genetic correlation between PRISM and pulmonary and extra-pulmonary traits. Phenome-wide association studies of top SNPs was performed. Results: 22 signals reached significance in the joint meta-analysis, including four signals novel for lung function. A strong genome-wide genetic correlation (rg) between PRISm and spirometric COPD (rg = 0.62, p-value <0.001) was observed, and genetic correlation with type II diabetes (rg = 0.12, p-value 0.007). PheWAS showed that 18 of 22 signals were associated with diabetic traits and 7 with blood pressure traits.Discussion: This is the first GWAS to successfully identify SNPs associated with PRISm. Four of the signals; rs7652391 (nearest gene MECOM), rs9431040 (HLX), rs62018863 (TMEM114) and rs185937162 (HLA-B) have not been described in association with lung function before, demonstrating the utility of using different lung function phenotypes in GWAS. Genetic factors associated with PRISm are strongly correlated with risk of both other lung diseases and extra-pulmonary co-morbidity.",
author = "Higbee, {Daniel H.} and Alvin Lirio and Fergus Hamilton and Raquel Granell and Wyss, {Annah B} and London, {Stephanie J} and Bartz, {Traci M} and Gharib, {Sina A} and Cho, {Michael H} and Emily Wan and Edwin Silverman and Crapo, {James D} and Jesus Lominchar and Torben Hansen and Niels Grarup and Thomas Dantoft and Line K{\aa}rhus and Allan Linneberg and O'Connor, {George T} and Jos{\'e}e Dupuis and Hanfie Xu and {De Vries}, {Maaike M} and Xiaowei Hu and Rich, {Stephen S} and Barr, {R Graham} and Ani Manichaikul and Wijnant, {Sarah R A} and Brusselle, {Guy G} and Lies Lahouse and Xuan Li and {Hern{\'a}ndez Cordero}, {Ana I} and Ma{\textquoteright}en Obeidat and {D Sin}, Don and Sarah Harris and Paul Redmond and Adele Taylor and Cox, {Simon R} and Williams, {Alexander T} and Nick Shrine and Catherine John and Guyatt, {Anna L} and Hall, {Ian P} and {Davey Smith}, George and Tobin, {Martin D} and Dodd, {James W}",
note = "Acknowledgements: This research has been conducted using the UK Biobank Resource under application number 55521. We acknowledge Marike Boezen's contribution to this paper, who sadly died before its completion. EXCEED is supported by the University of Leicester, the NIHR Leicester Respiratory Biomedical Research Centre, by Wellcome (202849, https://doi.org/10.35802/202849) and by Cohort Access fees from studies funded by the Medical Research Council (MRC), the Biotechnology and Biological Sciences Research Council (BBRSC), National Institute for Health and Care Research (NIHR), the UK Space Agency and GlaxoSmithKline. It was previously supported by MRC grant G0902313. This work is supported by BREATHE – The Health Data Research Hub for Respiratory Health (UKR_PC_19004) in partnership with SAIL Databank. We also thank all participants and staff who have contributed their time to the study. The authors thank all LBC1936 study participants and research team members who have contributed, and continue to contribute, to ongoing studies. Support statement: This work was supported by the Medical Research Council (MRC) and the University of Bristol (MC_UU_00011) and MRC CARP Fellowship (MR/T005114/1). J.W. Dodd is supported by the National Institute for Health and Care Research (NIHR) Bristol Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The Agricultural Lung Health Study (ALHS) was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (NIEHS) (Z01-ES102385, Z01-ES049030, Z01-ES043012, and for ABW, contract number HHSN273201600003I) and the National Cancer Institute (Z01-CP010119). ALHS was also supported in part by American Recovery and Reinvestment Act (ARRA) funds through NIEHS contract number N01-ES-55546. The ALHS thank the numerous study staff at Social and Scientific Systems, Inc. who played a role in the data collection, and acknowledge Jianping Jin (Westat) for expert computational assistance on the ALHS and Nathan Gaddis (RTI) for assistance performing genotype QC and HRC imputation for the ALHS. The research was partially supported by the NIHR Leicester Biomedical Research Centre and through an NIHR Senior Investigator Award to M.D. Tobin; views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The funders had no role in the design of the study. This research was funded in whole, or in part, by the Wellcome Trust: Wellcome Trust Investigator Award (WT202849/Z/16/Z, M.D. Tobin) and Wellcome Trust Discovery Award (WT225221/Z/22/Z, M.D. Tobin and A.L. Guyatt). MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Analyses for this project were supported by NIH/NHLBI R01-HL153248. The MESA Lung Study is supported by R01-HL077612 and R01-HL093081. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881 and DK063491. This publication was developed under Science to Achieve Results (STAR) research assistance agreements, No. RD831697 (MESA Air) and RD-83830001 (MESA Air Next Stage), awarded by the US Environmental Protection Agency (EPA). It has not been formally reviewed by the EPA. The views expressed in this document are solely those of the authors and the EPA does not endorse any products or commercial services mentioned in this publication. Funding for SHARe genotyping was provided by NHLBI contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, CA, USA) and the Broad Institute of Harvard and MIT (Boston, MA, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The authors acknowledge Research Computing at The University of Virginia for providing computational resources and technical support that have contributed to the results reported within this publication (https://rc.virginia.edu). J.V.T. Lominchar, T. Hansen and N. Grarup were funded by the Novo Nordisk Foundation (grant number NNF18CC0034900). Cardiovascular Health Study: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086 and 75N92021D00006; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393 and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, Clinical and Translational Science Institute grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. LBC1936 is supported by the Biotechnology and Biological Sciences Research Council (BBSRC), and the Economic and Social Research Council (BB/W008793/1) (which supports S.E. Harris), Age UK (Disconnected Mind project) and the University of Edinburgh. S.R. Cox is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (221890/Z/20/Z). Genotyping of the cohorts was funded by the BBSRC (BB/F019394/1). The Rotterdam Study is supported by the Erasmus MC and Erasmus University Rotterdam; the Netherlands Organisation for Scientific Research (NWO) (grant 918-46-615); the Netherlands Organisation for Health Research and Development (ZonMW); the Research Institute for Diseases in the Elderly (RIDE); the Netherlands Genomics Initiative; the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission (DG XII; grant 601055); and the Municipality of Rotterdam. S.R.A. Wijnant was funded by the “Funds for Scientific Research Flanders (Fonds voor Wetenschappelijk Onderzoek Vlaanderen)”, grant 3G037618. The COPDGene project was supported by award number U01 HL089897 and award number U01 HL089856 from the NHLBI. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NHLBI or the NIH. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer and Sunovion. Funding information for this article has been deposited with the Crossref Funder Registry.",
year = "2024",
month = jan,
doi = "10.1183/13993003.00337-2023",
language = "English",
volume = "63",
journal = "European Respiratory Journal",
issn = "0903-1936",
publisher = "European Respiratory Society",
}