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

Daniel H. Higbee; Alvin Lirio; Fergus Hamilton; Raquel Granell; Annah B. Wyss; Stephanie J. London; Traci M. Bartz; Sina A. Gharib; Michael H. Cho; Emily Wan; Edwin Silverman; James D. Crapo; Jesus V.T. Lominchar; Torben Hansen; Niels Grarup; Thomas Dantoft; Line Kårhus; Allan Linneberg; George T. O’Connor; Josée Dupuis; Hanfie Xu; Maaike M. De Vries; Xiaowei Hu; Stephen S. Rich; R. Graham Barr; Ani Manichaikul; Sara R.A. Wijnant; Guy G. Brusselle; Lies Lahousse; Xuan Li; Ana I. Hernández Cordero; Maen Obeidat; Don D. Sin; Sarah E. Harris; Paul Redmond; Adele M. Taylor; Simon R. Cox; Alexander T. Williams; Nick Shrine; Catherine John; Anna L. Guyatt; Ian P. Hall; George Davey Smith; Martin D. Tobin; James W. Dodd

doi:10.1183/13993003.00337-2023

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

Daniel H. Higbee, Alvin Lirio, Fergus Hamilton, Raquel Granell, Annah B. Wyss, Stephanie J. London, Traci M. Bartz, Sina A. Gharib, Michael H. Cho, Emily Wan, Edwin Silverman, James D. Crapo, Jesus V.T. Lominchar, Torben Hansen, Niels Grarup, Thomas Dantoft, Line Kårhus, Allan Linneberg, George T. O’Connor, Josée DupuisHanfie Xu, Maaike M. De Vries, Xiaowei Hu, Stephen S. Rich, R. Graham Barr, Ani Manichaikul, Sara R.A. Wijnant, Guy G. Brusselle, Lies Lahousse, Xuan Li, Ana I. Hernández Cordero, Maen Obeidat, Don D. Sin, Sarah E. Harris, Paul Redmond, Adele M. Taylor, Simon R. Cox, Alexander T. Williams, Nick Shrine, Catherine John, Anna L. Guyatt, Ian P. Hall, George Davey Smith, Martin D. Tobin, James W. Dodd^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

9 Citations (Scopus)

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.

Original language	English
Article number	2300337
Number of pages	12
Journal	European Respiratory Journal
Volume	63
Issue number	1
Early online date	14 Dec 2023
DOIs	https://doi.org/10.1183/13993003.00337-2023
Publication status	Published - Jan 2024

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Publisher Copyright:
©ERS 2024.

Research Groups and Themes

Bristol Population Health Science Institute
Academic Respiratory Unit

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Higbee, D. H., Lirio, A., Hamilton, F., Granell, R., Wyss, A. B., London, S. J., Bartz, T. M., Gharib, S. A., Cho, M. H., Wan, E., Silverman, E., Crapo, J. D., Lominchar, J. V. T., Hansen, T., Grarup, N., Dantoft, T., Kårhus, L., Linneberg, A., O’Connor, G. T., ... Dodd, J. W. (2024). Genome-wide association study of preserved ratio impaired spirometry (PRISm). European Respiratory Journal, 63(1), Article 2300337. https://doi.org/10.1183/13993003.00337-2023

@article{0cd68ec731394cfca88a3b4c3390688f,

title = "Genome-wide association study of preserved ratio impaired spirometry (PRISm)",

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 (rg) between PRISm and spirometric COPD (rg=0.62, p<0.001) was observed, and genetic correlation with type 2 diabetes (rg=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.",

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 Lominchar, {Jesus V.T.} and Torben Hansen and Niels Grarup and Thomas Dantoft and Line K{\aa}rhus and Allan Linneberg and O{\textquoteright}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, {Sara R.A.} and Brusselle, {Guy G.} and Lies Lahousse and Xuan Li and {Hern{\'a}ndez Cordero}, {Ana I.} and Maen Obeidat and Sin, {Don D.} and Harris, {Sarah E.} and Paul Redmond and Taylor, {Adele M.} and Cox, {Simon R.} and Williams, {Alexander T.} and Nick Shrine and Catherine John and Guyatt, {Anna L.} and Hall, {Ian P.} and Smith, {George Davey} and Tobin, {Martin D.} and Dodd, {James W.}",

note = "Publisher Copyright: {\textcopyright}ERS 2024.",

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",

number = "1",

}

Higbee, DH, Lirio, A, Hamilton, F , Granell, R, Wyss, AB, London, SJ, Bartz, TM, Gharib, SA, Cho, MH, Wan, E, Silverman, E, Crapo, JD, Lominchar, JVT, Hansen, T, Grarup, N, Dantoft, T, Kårhus, L, Linneberg, A, O’Connor, GT, Dupuis, J, Xu, H, De Vries, MM, Hu, X, Rich, SS, Barr, RG, Manichaikul, A, Wijnant, SRA, Brusselle, GG, Lahousse, L, Li, X, Hernández Cordero, AI, Obeidat, M, Sin, DD, Harris, SE, Redmond, P, Taylor, AM, Cox, SR, Williams, AT, Shrine, N, John, C, Guyatt, AL, Hall, IP, Smith, GD, Tobin, MD & Dodd, JW 2024, 'Genome-wide association study of preserved ratio impaired spirometry (PRISm)', European Respiratory Journal, vol. 63, no. 1, 2300337. https://doi.org/10.1183/13993003.00337-2023

TY - JOUR

T1 - Genome-wide association study of preserved ratio impaired spirometry (PRISm)

AU - Higbee, Daniel H.

AU - Lirio, Alvin

AU - Hamilton, Fergus

AU - Granell, Raquel

AU - Wyss, Annah B.

AU - London, Stephanie J.

AU - Bartz, Traci M.

AU - Gharib, Sina A.

AU - Cho, Michael H.

AU - Wan, Emily

AU - Silverman, Edwin

AU - Crapo, James D.

AU - Lominchar, Jesus V.T.

AU - Hansen, Torben

AU - Grarup, Niels

AU - Dantoft, Thomas

AU - Kårhus, Line

AU - Linneberg, Allan

AU - O’Connor, George T.

AU - Dupuis, Josée

AU - Xu, Hanfie

AU - De Vries, Maaike M.

AU - Hu, Xiaowei

AU - Rich, Stephen S.

AU - Barr, R. Graham

AU - Manichaikul, Ani

AU - Wijnant, Sara R.A.

AU - Brusselle, Guy G.

AU - Lahousse, Lies

AU - Li, Xuan

AU - Hernández Cordero, Ana I.

AU - Obeidat, Maen

AU - Sin, Don D.

AU - Harris, Sarah E.

AU - Redmond, Paul

AU - Taylor, Adele M.

AU - Cox, Simon R.

AU - Williams, Alexander T.

AU - Shrine, Nick

AU - John, Catherine

AU - Guyatt, Anna L.

AU - Hall, Ian P.

AU - Smith, George Davey

AU - Tobin, Martin D.

AU - Dodd, James W.

PY - 2024/1

Y1 - 2024/1

N2 - 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 (rg) between PRISm and spirometric COPD (rg=0.62, p<0.001) was observed, and genetic correlation with type 2 diabetes (rg=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.

AB - 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 (rg) between PRISm and spirometric COPD (rg=0.62, p<0.001) was observed, and genetic correlation with type 2 diabetes (rg=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.

UR - http://www.scopus.com/inward/record.url?scp=85181773328&partnerID=8YFLogxK

U2 - 10.1183/13993003.00337-2023

DO - 10.1183/13993003.00337-2023

M3 - Article (Academic Journal)

C2 - 38097206

AN - SCOPUS:85181773328

SN - 0903-1936

VL - 63

JO - European Respiratory Journal

JF - European Respiratory Journal

IS - 1

M1 - 2300337

ER -

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

Abstract

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

Abstract

Bibliographical note

Research Groups and Themes

UN SDGs

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Integrative Epidemiology Unit

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