Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function

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 & 61 others 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, Ian P. Hall, Patricia A. Cassano

Research output: Contribution to journalArticle

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Abstract

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 (FEV 1) 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 × 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 = 2.18 × 10-8) 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.

Original languageEnglish (US)
Article numbere100776
JournalPloS one
Volume9
Issue number7
DOIs
StatePublished - Jul 1 2014

Fingerprint

Genome-Wide Association Study
lung function
Meta-Analysis
Genes
Association reactions
Lung
loci
Genetic Loci
meta-analysis
Interleukin-16
Chromosomes
cohort studies
Gene expression
Cohort Studies
Genotype
Gene Expression
Chromosomes, Human, Pair 15
lungs
Chromosomes, Human, Pair 11
chromosomes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Tang, W., Kowgier, M., Loth, D. W., Soler Artigas, M., Joubert, B. R., Hodge, E., ... Cassano, P. A. (2014). Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function. PloS one, 9(7), [e100776]. https://doi.org/10.1371/journal.pone.0100776

Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function. / 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.

In: PloS one, Vol. 9, No. 7, e100776, 01.07.2014.

Research output: Contribution to journalArticle

Tang, W, Kowgier, M, Loth, DW, Soler Artigas, M, Joubert, BR, Hodge, E, Gharib, SA, Smith, AV, Ruczinski, I, Gudnason, V, Mathias, RA, Harris, TB, Hansel, NN, Launer, LJ, Barnes, KC, Hansen, JG, Albrecht, E, Aldrich, MC, Allerhand, M, Barr, RG, Brusselle, GG, Couper, DJ, Curjuric, I, Davies, G, Deary, IJ, Dupuis, J, Fall, T, Foy, M, Franceschini, N, Gao, W, Gläser, S, Gu, X, Hancock, DB, Heinrich, J, Hofman, A, Imboden, M, Ingelsson, E, James, A, Karrasch, S, Koch, B, Kritchevsky, SB, Kumar, A, Lahousse, L, Li, G, Lind, L, Lindgren, C, Liu, Y, Lohman, K, Lumley, T, McArdle, WL, Meibohm, B, Morris, AP, Morrison, AC, Musk, B, North, KE, Palmer, LJ, Probst-Hensch, NM, Psaty, BM, Rivadeneira, F, Rotter, JI, Schulz, H, Smith, LJ, Sood, A, Starr, JM, Strachan, DP, Teumer, A, Uitterlinden, AG, Völzke, H, Voorman, A, Wain, LV, Wells, MT, Wilk, JB, Williams, OD, Heckbert, SR, Stricker, BH, London, SJ, Fornage, M, Tobin, MD, O'Connor, GT, Hall, IP & Cassano, PA 2014, 'Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function', PloS one, vol. 9, no. 7, e100776. https://doi.org/10.1371/journal.pone.0100776
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. / Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function. In: PloS one. 2014 ; Vol. 9, No. 7.
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title = "Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function",
abstract = "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 (FEV 1) 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 × 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 = 2.18 × 10-8) 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.",
author = "Wenbo Tang and Matthew Kowgier and Loth, {Daan W.} and {Soler Artigas}, Mar{\'i}a and Joubert, {Bonnie R.} and Emily Hodge and Gharib, {Sina A.} and Smith, {Albert V.} and Ingo Ruczinski and Vilmundur Gudnason and Mathias, {Rasika A.} and Harris, {Tamara B.} and Hansel, {Nadia N.} and Launer, {Lenore J.} and Barnes, {Kathleen C.} and Hansen, {Joyanna G.} and Eva Albrecht and Aldrich, {Melinda C.} and Michael Allerhand and Barr, {R. Graham} and Brusselle, {Guy G.} and Couper, {David J.} and Ivan Curjuric and Gail Davies and Deary, {Ian J.} and Jos{\'e}e Dupuis and Tove Fall and Millennia Foy and Nora Franceschini and Wei Gao and Sven Gl{\"a}ser and Xiangjun Gu and Hancock, {Dana B.} and Joachim Heinrich and Albert Hofman and Medea Imboden and Erik Ingelsson and Alan James and Stefan Karrasch and Beate Koch and Kritchevsky, {Stephen B.} and Ashish Kumar and Lies Lahousse and Guo Li and Lars Lind and Cecilia Lindgren and Yongmei Liu and Kurt Lohman and Thomas Lumley and McArdle, {Wendy L.} and Bernd Meibohm and Morris, {Andrew P.} and Morrison, {Alanna C.} and Bill Musk and North, {Kari E.} and Palmer, {Lyle J.} and Probst-Hensch, {Nicole M.} and Psaty, {Bruce M.} and Fernando Rivadeneira and Rotter, {Jerome I.} and Holger Schulz and Smith, {Lewis J.} and Akshay Sood and Starr, {John M.} and Strachan, {David P.} and Alexander Teumer and Uitterlinden, {Andr{\'e} G.} and Henry V{\"o}lzke and Arend Voorman and Wain, {Louise V.} and Wells, {Martin T.} and Wilk, {Jemma B.} and Williams, {O. Dale} and Heckbert, {Susan R.} and Stricker, {Bruno H.} and London, {Stephanie J.} and Myriam Fornage and Tobin, {Martin D.} and O'Connor, {George T.} and Hall, {Ian P.} and Cassano, {Patricia A.}",
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TY - JOUR

T1 - Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function

AU - Tang, Wenbo

AU - Kowgier, Matthew

AU - Loth, Daan W.

AU - Soler Artigas, María

AU - Joubert, Bonnie R.

AU - Hodge, Emily

AU - Gharib, Sina A.

AU - Smith, Albert V.

AU - Ruczinski, Ingo

AU - Gudnason, Vilmundur

AU - Mathias, Rasika A.

AU - Harris, Tamara B.

AU - Hansel, Nadia N.

AU - Launer, Lenore J.

AU - Barnes, Kathleen C.

AU - Hansen, Joyanna G.

AU - Albrecht, Eva

AU - Aldrich, Melinda C.

AU - Allerhand, Michael

AU - Barr, R. Graham

AU - Brusselle, Guy G.

AU - Couper, David J.

AU - Curjuric, Ivan

AU - Davies, Gail

AU - Deary, Ian J.

AU - Dupuis, Josée

AU - Fall, Tove

AU - Foy, Millennia

AU - Franceschini, Nora

AU - Gao, Wei

AU - Gläser, Sven

AU - Gu, Xiangjun

AU - Hancock, Dana B.

AU - Heinrich, Joachim

AU - Hofman, Albert

AU - Imboden, Medea

AU - Ingelsson, Erik

AU - James, Alan

AU - Karrasch, Stefan

AU - Koch, Beate

AU - Kritchevsky, Stephen B.

AU - Kumar, Ashish

AU - Lahousse, Lies

AU - Li, Guo

AU - Lind, Lars

AU - Lindgren, Cecilia

AU - Liu, Yongmei

AU - Lohman, Kurt

AU - Lumley, Thomas

AU - McArdle, Wendy L.

AU - Meibohm, Bernd

AU - Morris, Andrew P.

AU - Morrison, Alanna C.

AU - Musk, Bill

AU - North, Kari E.

AU - Palmer, Lyle J.

AU - Probst-Hensch, Nicole M.

AU - Psaty, Bruce M.

AU - Rivadeneira, Fernando

AU - Rotter, Jerome I.

AU - Schulz, Holger

AU - Smith, Lewis J.

AU - Sood, Akshay

AU - Starr, John M.

AU - Strachan, David P.

AU - Teumer, Alexander

AU - Uitterlinden, André G.

AU - Völzke, Henry

AU - Voorman, Arend

AU - Wain, Louise V.

AU - Wells, Martin T.

AU - Wilk, Jemma B.

AU - Williams, O. Dale

AU - Heckbert, Susan R.

AU - Stricker, Bruno H.

AU - London, Stephanie J.

AU - Fornage, Myriam

AU - Tobin, Martin D.

AU - O'Connor, George T.

AU - Hall, Ian P.

AU - Cassano, Patricia A.

PY - 2014/7/1

Y1 - 2014/7/1

N2 - 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 (FEV 1) 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 × 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 = 2.18 × 10-8) 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.

AB - 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 (FEV 1) 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 × 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 = 2.18 × 10-8) 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.

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U2 - 10.1371/journal.pone.0100776

DO - 10.1371/journal.pone.0100776

M3 - Article

VL - 9

JO - PLoS One

JF - PLoS One

SN - 1932-6203

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ER -