Meta-Analysis

. 2024 Jan 4;63(1):2300337.

doi: 10.1183/13993003.00337-2023. Print 2024 Jan.

Genome-wide association study of preserved ratio impaired spirometry (PRISm)

Daniel H Higbee^{1

2}, Alvin Lirio³, Fergus Hamilton¹, Raquel Granell¹, Annah B Wyss⁴, Stephanie J London⁴, Traci M Bartz⁵, Sina A Gharib⁶, Michael H Cho^{7

8}, Emily Wan^{7

8

9}, Edwin Silverman⁹, James D Crapo¹⁰, Jesus V T Lominchar¹¹, Torben Hansen¹¹, Niels Grarup¹¹, Thomas Dantoft¹², Line Kårhus¹², Allan Linneberg¹², George T O'Connor^{13

14}, Josée Dupuis¹⁵, Hanfie Xu¹⁶, Maaike M De Vries^{17

18}, Xiaowei Hu¹⁹, Stephen S Rich¹⁹, R Graham Barr²⁰, Ani Manichaikul¹⁹, Sara R A Wijnant^{21

22

23}, Guy G Brusselle^{23

24}, Lies Lahousse^{21

22}, Xuan Li²⁵, Ana I Hernández Cordero²⁵, Ma'en Obeidat²⁵, Don D Sin^{25

26}, Sarah E Harris²⁷, Paul Redmond²⁷, Adele M Taylor²⁷, Simon R Cox²⁷, Alexander T Williams³, Nick Shrine³, Catherine John³, Anna L Guyatt³, Ian P Hall²⁸, George Davey Smith¹, Martin D Tobin^{3

29

30}, James W Dodd^{31

2

30}

Affiliations

¹ MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK.
² Academic Respiratory Unit, University of Bristol, Southmead Hospital, Bristol, UK.
³ Department of Population Health Sciences, University of Leicester, Leicester, UK.
⁴ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
⁵ Cardiovascular Health Research Unit, Departments of Biostatistics and Medicine, University of Washington, Seattle, WA, USA.
⁶ Computational Medicine Core, Center for Lung Biology, UW Medicine Sleep Center, Department of Medicine, University of Washington, Seattle, WA, USA.
⁷ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁸ Harvard Medical School, Boston, MA, USA.
⁹ Pulmonary and Critical Care Section, Department of Medicine, VA Boston Healthcare System, Boston, MA, USA.
¹⁰ Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO, USA.
¹¹ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹² Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark.
¹³ Pulmonary Center, School of Medicine, Boston University, Boston, MA, USA.
¹⁴ Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Boston Medical Center, Boston, MA, USA.
¹⁵ Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada.
¹⁶ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹⁷ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹⁸ Groningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹⁹ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
²⁰ Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
²¹ Department of Bioanalysis, Ghent University, Ghent, Belgium.
²² Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
²³ Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
²⁴ Department of Epidemiology, Department of Respiratory Medicine, Erasmus MC, Rotterdam, The Netherlands.
²⁵ Centre for Heart Lung Innovation, University of British Columbia, St. Paul's Hospital, Vancouver, BC, Canada.
²⁶ Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
²⁷ Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, UK.
²⁸ University of Nottingham and NIHR Nottingham Biomedical Research Centre, Nottingham, UK.
²⁹ Leicester NIHR Biomedical Research Centre, Leicester, UK.
³⁰ Joint senior authors.
³¹ MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK james.dodd@bristol.ac.uk.

PMID: 38097206
PMCID: PMC10765494
DOI: 10.1183/13993003.00337-2023

Meta-Analysis

Genome-wide association study of preserved ratio impaired spirometry (PRISm)

Daniel H Higbee et al. Eur Respir J. 2024.

. 2024 Jan 4;63(1):2300337.

doi: 10.1183/13993003.00337-2023. Print 2024 Jan.

Authors

Affiliations

¹ MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK.
² Academic Respiratory Unit, University of Bristol, Southmead Hospital, Bristol, UK.
³ Department of Population Health Sciences, University of Leicester, Leicester, UK.
⁴ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
⁵ Cardiovascular Health Research Unit, Departments of Biostatistics and Medicine, University of Washington, Seattle, WA, USA.
⁶ Computational Medicine Core, Center for Lung Biology, UW Medicine Sleep Center, Department of Medicine, University of Washington, Seattle, WA, USA.
⁷ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁸ Harvard Medical School, Boston, MA, USA.
⁹ Pulmonary and Critical Care Section, Department of Medicine, VA Boston Healthcare System, Boston, MA, USA.
¹⁰ Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO, USA.
¹¹ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹² Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark.
¹³ Pulmonary Center, School of Medicine, Boston University, Boston, MA, USA.
¹⁴ Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Boston Medical Center, Boston, MA, USA.
¹⁵ Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada.
¹⁶ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹⁷ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹⁸ Groningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹⁹ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
²⁰ Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
²¹ Department of Bioanalysis, Ghent University, Ghent, Belgium.
²² Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
²³ Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
²⁴ Department of Epidemiology, Department of Respiratory Medicine, Erasmus MC, Rotterdam, The Netherlands.
²⁵ Centre for Heart Lung Innovation, University of British Columbia, St. Paul's Hospital, Vancouver, BC, Canada.
²⁶ Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
²⁷ Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, UK.
²⁸ University of Nottingham and NIHR Nottingham Biomedical Research Centre, Nottingham, UK.
²⁹ Leicester NIHR Biomedical Research Centre, Leicester, UK.
³⁰ Joint senior authors.
³¹ MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK james.dodd@bristol.ac.uk.

PMID: 38097206
PMCID: PMC10765494
DOI: 10.1183/13993003.00337-2023

Abstract

Background: Preserved ratio impaired spirometry (PRISm) is defined as a forced expiratory volume in 1 s (FEV₁) <80% predicted and FEV₁/forced vital capacity ≥0.70. PRISm is associated with respiratory symptoms and comorbidities. Our objective was to discover novel genetic signals for PRISm and see if they provide insight into the pathogenesis of PRISm and associated comorbidities.

Methods: We undertook a genome-wide association study (GWAS) of PRISm in UK Biobank participants (Stage 1), and selected single nucleotide polymorphisms (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 extrapulmonary traits. Phenome-wide association studies of top SNPs were performed.

Results: 22 signals reached significance in the joint meta-analysis, including four signals novel for lung function. A strong genome-wide genetic correlation (r_g) between PRISm and spirometric COPD (r_g=0.62, p<0.001) was observed, and genetic correlation with type 2 diabetes (r_g=0.12, p=0.007). Phenome-wide association studies showed that 18 of 22 signals were associated with diabetic traits and seven with blood pressure traits.

Conclusion: 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 extrapulmonary comorbidity.

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Conflict of interest statement

Conflict of interest: S.J. London reports support for the present work from National Institutes of Health (NIH), USA. M.H. Cho reports support for the present work from the National Heart, Lung, and Blood Institute (NHLBI) and grants from Bayer outside the submitted work. E. Wan reports grants from US Department of Veterans Affairs Research and Development, outside the submitted work. E. Silverman reports support for the present work from NIH (grant U01 HL089856) and has received institutional grant support from Bayer outside the submitted work. J.D. Crapo reports grants from NIH (U01 HL089897, U01 HL089856); and a leadership role as Chair of Board of Directors of COPD Foundation outside the submitted work. X. Hu reports support for the present manuscript from NIH/NHLBI (R01-HL153248), as well as travel support. L. Lahousse reports consulting fees from AstraZeneca and lecture honoraria from IPSA vzw and Chiesi, outside the submitted work. D.D. Sin reports lecture honoraria from GlaxoSmithKline, AstraZeneca and Boehringer Ingelheim, outside the submitted work. S.E. Harris reports support for the current manuscript from Biotechnology and Biological Sciences Research Council, and the Economic and Social Research Council (BB/W008793/1). M.D. Tobin, A.L. Guyatt and C. John have a funded research collaboration with Orion for collaborative research projects outside the submitted work. G. Davey Smith reports grants from MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1) and Scientific Advisory Board Membership for Relation Therapeutics and Insitro, outside the submitted work. M.D. Tobin reports support for the present work from Wellcome Trust, NIHR Leicester Biomedical Research Centre and National Institute of Health and Care Research, and has previously received funding from GlaxoSmithKline for collaborative research projects outside of the submitted work. J.W. Dodd declares he has received honoraria for participating in advisory boards and given lectures at meetings supported by GlaxoSmithKline, Boehringer Ingelheim, Chiesi, AstraZeneca, Fisher & Paykel and Aerogen; he has received sponsorship for attending international scientific meetings from Chiesi; he has also taken part in asthma clinical trials sponsored by Sanofi, AstraZeneca and Chiesi for which his institution received remuneration. All other authors have nothing to disclose.

Figures

**FIGURE 1**
Participant selection flow chart. BMI: body mass index; PRISm: preserved ratio impaired spirometry; GWAS: genome-wide association study.

**FIGURE 2**
Manhattan plot of discovery genome-wide association study after linkeage disequilibrium score regression filtering and adjustment.

**FIGURE 3**
Flow chart of single nucleotide polymorphisms (SNPs) analysed. GWAS: genome-wide association study; PRISm: preserved ratio impaired spirometry; LDSC: linkeage disequilibrium score regression; MAF: minor allele frequency; OR: odds ratio.

See this image and copyright information in PMC

Comment in

Some future directions for genome-wide association studies of preserved ratio impaired spirometry.
Jin Z, Wang G. Jin Z, et al. Eur Respir J. 2024 Mar 7;63(3):2400142. doi: 10.1183/13993003.00142-2024. Print 2024 Mar. Eur Respir J. 2024. PMID: 38453246 No abstract available.

References

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Genome-wide association study of preserved ratio impaired spirometry (PRISm)

Affiliations

Genome-wide association study of preserved ratio impaired spirometry (PRISm)

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

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Research Materials