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Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function

Chen, Lin; Tang, Wenbo; Kowgier, Matthew; Loth, Daan W.; Soler Artigas, María; Joubert, Bonnie R.; Hodge, Emily; Gharib, Sina A.; Smith, Albert V.; Ruczinski, Ingo; Gudnason, Vilmundur; Mathias, Rasika A.; Harris, Tamara B.; Hansel, Nadia N.; Launer, Lenore J.; Barnes, Kathleen C.; Hansen, Joyanna G.; Albrecht, Eva; Aldrich, Melinda C.; Allerhand, Michael; Barr, R. Graham; Brusselle, Guy G.; Couper, David J.; Curjuric, Ivan; Davies, Gail; Deary, Ian J.; Dupuis, Josée; Fall, Tove; Foy, Millennia; Franceschini, Nora; Gao, Wei; Gläser, Sven; Gu, Xiangjun; Hancock, Dana B.; Heinrich, Joachim; Hofman, Albert; Imboden, Medea; Ingelsson, Erik; James, Alan; Karrasch, Stefan; Koch, Beate; Kritchevsky, Stephen B.; Kumar, Ashish; Lahousse, Lies; Li, Guo; Lind, Lars; Lindgren, Cecilia; Liu, Yongmei; Lohman, Kurt; Lumley, Thomas; McArdle, Wendy L.; Meibohm, Bernd; Morris, Andrew P.; Morrison, Alanna C.; Musk, Bill; North, Kari E.; Palmer, Lyle J.; Probst-Hensch, Nicole M.; Psaty, Bruce M.; Rivadeneira, Fernando; Rotter, Jerome I.; Schulz, Holger; Smith, Lewis J.; Sood, Akshay; Starr, John M.; Strachan, David P.; Teumer, Alexander; Uitterlinden, André G.; Völzke, Henry; Voorman, Arend; Wain, Louise V.; Wells, Martin T.; Wilk, Jemma B.; Williams, O. Dale; Heckbert, Susan R.; Stricker, Bruno H.; London, Stephanie J.; Fornage, Myriam; Tobin, Martin D.; O′Connor, George T.; Hall, Ian P.; Cassano, Patricia A.


Lin Chen

Wenbo Tang

Matthew Kowgier

Daan W. Loth

María Soler Artigas

Bonnie R. Joubert

Emily Hodge

Sina A. Gharib

Albert V. Smith

Ingo Ruczinski

Vilmundur Gudnason

Rasika A. Mathias

Tamara B. Harris

Nadia N. Hansel

Lenore J. Launer

Kathleen C. Barnes

Joyanna G. Hansen

Eva Albrecht

Melinda C. Aldrich

Michael Allerhand

R. Graham Barr

Guy G. Brusselle

David J. Couper

Ivan Curjuric

Gail Davies

Ian J. Deary

Josée Dupuis

Tove Fall

Millennia Foy

Nora Franceschini

Wei Gao

Sven Gläser

Xiangjun Gu

Dana B. Hancock

Joachim Heinrich

Albert Hofman

Medea Imboden

Erik Ingelsson

Alan James

Stefan Karrasch

Beate Koch

Stephen B. Kritchevsky

Ashish Kumar

Lies Lahousse

Guo Li

Lars Lind

Cecilia Lindgren

Yongmei Liu

Kurt Lohman

Thomas Lumley

Wendy L. McArdle

Bernd Meibohm

Andrew P. Morris

Alanna C. Morrison

Bill Musk

Kari E. North

Lyle J. Palmer

Nicole M. Probst-Hensch

Bruce M. Psaty

Fernando Rivadeneira

Jerome I. Rotter

Holger Schulz

Lewis J. Smith

Akshay Sood

John M. Starr

David P. Strachan

Alexander Teumer

André G. Uitterlinden

Henry Völzke

Arend Voorman

Louise V. Wain

Martin T. Wells

Jemma B. Wilk

O. Dale Williams

Susan R. Heckbert

Bruno H. Stricker

Stephanie J. London

Myriam Fornage

Martin D. Tobin

George T. O′Connor

Professor of Molecular Medicine

Patricia A. Cassano


Lin Chen


Background: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.
Methods: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.
Results: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 6 10-7). In addition, meta-analysis using the five cohorts with $3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18610-8) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.
Conclusions: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.


Chen, L., Tang, W., Kowgier, M., Loth, D. W., Soler Artigas, M., Joubert, B. R., …Cassano, P. A. (2014). Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function. PLoS ONE, 9(7),

Journal Article Type Article
Acceptance Date Apr 17, 2014
Online Publication Date Jul 1, 2014
Publication Date Jul 1, 2014
Deposit Date Jul 21, 2017
Publicly Available Date Jul 21, 2017
Journal PLoS ONE
Electronic ISSN 1932-6203
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 9
Issue 7
Article Number e100776
Public URL
Publisher URL
Copyright Statement Copyright information regarding this work can be found at the following address:


10.1371_journal.pone.0100776.pdf (893 Kb)

Copyright Statement
Copyright information regarding this work can be found at the following address:

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