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

WB Tang; M Kowgier; Daan Loth; MS Artigas; BR Joubert; E Hodge; SA Gharib; AV Smith; I Ruczinski; V Gudnason; RA Mathias; TB Harris; NN Hansel; LJ (Lenore) Launer; KC Barnes; JG Hansen; E Albrecht; MC Aldrich; M Allerhand; RG Barr; Guy Brusselle; DJ Couper; I Curjuric; G Davies; IJ Deary; J Dupuis; T Fall; M Foy; N Franceschini; W Gao; S Glaser; XJ Gu; DB Hancock; J (Joachim) Heinrich; Bert Hofman; M Imboden; E Ingelsson; A James; S Karrasch; B Koch; SB Kritchevsky; A Kumar; Lies Lahousse; G Li; L Lind; C Lindgren; YM Liu; K Lohman; T Lumley; WL McArdle; B Meibohm; AP Morris; AC Morrison; B Musk; KE North; LJ Palmer; NM Probst-Hensch; BM Psaty; Fernando Rivadeneira; JI Rotter; H Schulz; LJ Smith; A Sood; JM Starr; DP Strachan; A Teumer; André Uitterlinden; H Volzke; A Voorman; LV Wain; MT Wells; JB Wilk; OD Williams; SR Heckbert; Bruno Stricker; SJ London; M Fornage; MD Tobin; GT O'Connor; IP Hall; PA Cassano

doi:10.1371/journal.pone.0100776

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

WB Tang, M Kowgier, Daan Loth, MS Artigas, BR Joubert, E Hodge, SA Gharib, AV Smith, I Ruczinski, V Gudnason, RA Mathias, TB Harris, NN Hansel, LJ (Lenore) Launer, KC Barnes, JG Hansen, E Albrecht, MC Aldrich, M Allerhand, RG BarrGuy Brusselle, DJ Couper, I Curjuric, G Davies, IJ Deary, J Dupuis, T Fall, M Foy, N Franceschini, W Gao, S Glaser, XJ Gu, DB Hancock, J (Joachim) Heinrich, Bert Hofman, M Imboden, E Ingelsson, A James, S Karrasch, B Koch, SB Kritchevsky, A Kumar, Lies Lahousse, G Li, L Lind, C Lindgren, YM Liu, K Lohman, T Lumley, WL McArdle, B Meibohm, AP Morris, AC Morrison, B Musk, KE North, LJ Palmer, NM Probst-Hensch, BM Psaty, Fernando Rivadeneira, JI Rotter, H Schulz, LJ Smith, A Sood, JM Starr, DP Strachan, A Teumer, André Uitterlinden, H Volzke, A Voorman, LV Wain, MT Wells, JB Wilk, OD Williams, SR Heckbert, Bruno Stricker, SJ London, M Fornage, MD Tobin, GT O'Connor, IP Hall, PA Cassano

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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 (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 x 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 x 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 language	Undefined/Unknown
Journal	PLoS One (print)
Volume	9
Issue number	7
DOIs	https://doi.org/10.1371/journal.pone.0100776
Publication status	Published - 2014

Research programs

EMC MM-01-39-09-A
EMC MM-04-42-02
EMC NIHES-01-64-01

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Cite this

Tang, WB., Kowgier, M., Loth, D., Artigas, MS., 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., ... Cassano, PA. (2014). Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function. PLoS One (print), 9(7). https://doi.org/10.1371/journal.pone.0100776

@article{f4caee62e67444928414ed3072561594,

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 (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 x 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 x 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 = "WB Tang and M Kowgier and Daan Loth and MS Artigas and BR Joubert and E Hodge and SA Gharib and AV Smith and I Ruczinski and V Gudnason and RA Mathias and TB Harris and NN Hansel and Launer, {LJ (Lenore)} and KC Barnes and JG Hansen and E Albrecht and MC Aldrich and M Allerhand and RG Barr and Guy Brusselle and DJ Couper and I Curjuric and G Davies and IJ Deary and J Dupuis and T Fall and M Foy and N Franceschini and W Gao and S Glaser and XJ Gu and DB Hancock and Heinrich, {J (Joachim)} and Bert Hofman and M Imboden and E Ingelsson and A James and S Karrasch and B Koch and SB Kritchevsky and A Kumar and Lies Lahousse and G Li and L Lind and C Lindgren and YM Liu and K Lohman and T Lumley and WL McArdle and B Meibohm and AP Morris and AC Morrison and B Musk and KE North and LJ Palmer and NM Probst-Hensch and BM Psaty and Fernando Rivadeneira and JI Rotter and H Schulz and LJ Smith and A Sood and JM Starr and DP Strachan and A Teumer and Andr{\'e} Uitterlinden and H Volzke and A Voorman and LV Wain and MT Wells and JB Wilk and OD Williams and SR Heckbert and Bruno Stricker and SJ London and M Fornage and MD Tobin and GT O'Connor and IP Hall and PA Cassano",

year = "2014",

doi = "10.1371/journal.pone.0100776",

language = "Undefined/Unknown",

volume = "9",

journal = "PLoS One (print)",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "7",

}

Tang, WB, Kowgier, M, Loth, D, Artigas, MS, 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, G, Couper, DJ, Curjuric, I, Davies, G, Deary, IJ, Dupuis, J, Fall, T, Foy, M, Franceschini, N, Gao, W, Glaser, S, Gu, XJ, Hancock, DB, Heinrich, J, Hofman, B, Imboden, M, Ingelsson, E, James, A, Karrasch, S, Koch, B, Kritchevsky, SB, Kumar, A, Lahousse, L, Li, G, Lind, L, Lindgren, C, Liu, YM, 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, A, Volzke, H, Voorman, A, Wain, LV, Wells, MT, Wilk, JB, Williams, OD, Heckbert, SR, Stricker, B, 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 (print), vol. 9, no. 7. https://doi.org/10.1371/journal.pone.0100776

TY - JOUR

T1 - Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function

AU - Tang, WB

AU - Kowgier, M

AU - Loth, Daan

AU - Artigas, MS

AU - Joubert, BR

AU - Hodge, E

AU - Gharib, SA

AU - Smith, AV

AU - Ruczinski, I

AU - Gudnason, V

AU - Mathias, RA

AU - Harris, TB

AU - Hansel, NN

AU - Launer, LJ (Lenore)

AU - Barnes, KC

AU - Hansen, JG

AU - Albrecht, E

AU - Aldrich, MC

AU - Allerhand, M

AU - Barr, RG

AU - Brusselle, Guy

AU - Couper, DJ

AU - Curjuric, I

AU - Davies, G

AU - Deary, IJ

AU - Dupuis, J

AU - Fall, T

AU - Foy, M

AU - Franceschini, N

AU - Gao, W

AU - Glaser, S

AU - Gu, XJ

AU - Hancock, DB

AU - Heinrich, J (Joachim)

AU - Hofman, Bert

AU - Imboden, M

AU - Ingelsson, E

AU - James, A

AU - Karrasch, S

AU - Koch, B

AU - Kritchevsky, SB

AU - Kumar, A

AU - Lahousse, Lies

AU - Li, G

AU - Lind, L

AU - Lindgren, C

AU - Liu, YM

AU - Lohman, K

AU - Lumley, T

AU - McArdle, WL

AU - Meibohm, B

AU - Morris, AP

AU - Morrison, AC

AU - Musk, B

AU - North, KE

AU - Palmer, LJ

AU - Probst-Hensch, NM

AU - Psaty, BM

AU - Rivadeneira, Fernando

AU - Rotter, JI

AU - Schulz, H

AU - Smith, LJ

AU - Sood, A

AU - Starr, JM

AU - Strachan, DP

AU - Teumer, A

AU - Uitterlinden, André

AU - Volzke, H

AU - Voorman, A

AU - Wain, LV

AU - Wells, MT

AU - Wilk, JB

AU - Williams, OD

AU - Heckbert, SR

AU - Stricker, Bruno

AU - London, SJ

AU - Fornage, M

AU - Tobin, MD

AU - O'Connor, GT

AU - Hall, IP

AU - Cassano, PA

PY - 2014

Y1 - 2014

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 (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 x 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 x 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 (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 x 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 x 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.

U2 - 10.1371/journal.pone.0100776

DO - 10.1371/journal.pone.0100776

M3 - Article

C2 - 24983941

SN - 1932-6203

VL - 9

JO - PLoS One (print)

JF - PLoS One (print)

IS - 7

ER -