Epigenome-wide association study of lung function level and its change

Medea Imboden; Matthias Wielscher; Faisal I Rezwan; André F S Amaral; Emmanuel Schaffner; Ayoung Jeong; Anna Beckmeyer-Borowko; Sarah Harris; John Starr; Ian Deary; Claudia Flexeder; Melanie Waldenberger; Annette Peters; Holger Schulz; Su Chen; Sunny Shadia Khan; Wilifred J. J. Karmaus; Yu Jiang; Gertraud Erhart; Florian Kronenberg; Ryan Arathimos; Gemma C Sharp; Alexander John Henderson; Yu Fu; Päivi Piirilä; Kirsi H Pietiläinen; M Ollikainen; Asa Johansson; Ulf Gyllensten; Maaike de Vries; Diana A. van der Plaat; Kim de Jong; H. Marike Boezen; Ian P. Hall; Martin D Tobin; Marjo-Riitta Jarvelin; John W Holloway; Deborah L. Jarvis; Nicole M Probst-Hensch

doi:10.1183/13993003.00457-2019

Epigenome-wide association study of lung function level and its change

Medea Imboden, Matthias Wielscher, Faisal I Rezwan, André F S Amaral, Emmanuel Schaffner, Ayoung Jeong, Anna Beckmeyer-Borowko, Sarah Harris, John Starr, Ian Deary, Claudia Flexeder, Melanie Waldenberger, Annette Peters, Holger Schulz, Su Chen, Sunny Shadia Khan, Wilifred J. J. Karmaus, Yu Jiang, Gertraud Erhart, Florian KronenbergRyan Arathimos, Gemma C Sharp, Alexander John Henderson, Yu Fu, Päivi Piirilä, Kirsi H Pietiläinen, M Ollikainen, Asa Johansson, Ulf Gyllensten, Maaike de Vries, Diana A. van der Plaat, Kim de Jong, H. Marike Boezen, Ian P. Hall, Martin D Tobin, Marjo-Riitta Jarvelin, John W Holloway, Deborah L. Jarvis, Nicole M Probst-Hensch

Research output: Contribution to journal › Article › peer-review

Abstract

Previous reports link differential DNA methylation (DNAme) to environmental exposures which are associated with lung function. Direct evidence on lung function DNAme is however limited. We undertook an agnostic epigenome-wide association study (EWAS) on pre-bronchodilation lung function and its change in adults.In a discovery-replication EWAS design, DNAme in blood and spirometry were measured twice, six-to-15 years apart, in the same participants of three adult population-based discovery cohorts (n=2,043). Associated DNAme markers (P<5x10-7) were tested in seven replication cohorts (adult: n=3,327; childhood: n=420). Technical-bias adjusted residuals of a regression of the normalized absolute beta-values on control-probe-derived principle components were regressed on level and change of FEV1, FEV1/FVC and FVC in covariate-adjusted discovery EWAS. Inverse-variance weighted meta-analyses were performed on results from discovery and replication samples in all participants and never smokers.EWAS signals were enriched for smoking-related DNAme. We replicated 57 lung function DNAme in adult, but not childhood samples, all previously associated with smoking. Markers not previously associated with smoking failed replication. cg05575921 (AHRR) showed the statistically most significant association with cross-sectional lung function (FEV1/FVC: Pdiscovery=3.96x10-21 and Pcombined=7.22x10-50). A score combining ten DNAme markers previously reported to mediate the smoking effect on lung function was associated with lung function (FEV1/FVC: P=2.65x10-20).Our results reveal that lung function associated methylation signals in adults are predominantly smoking-related and possibly of clinical utility in identifying poor lung function and accelerated decline. Larger studies with more repeat time points are needed to identify lung function DNAme in never smokers and in children.

Original language	English
Journal	European Respiratory Journal
Volume	53
Issue number	5
Early online date	9 May 2019
DOIs	https://doi.org/10.1183/13993003.00457-2019
Publication status	E-pub ahead of print - 9 May 2019

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10.1183/13993003.00457-2019

ImbodenEtalERJ2019StudyOfLungfunctionLevelAndItsChange
This is an author-submitted, peer-reviewed version of a manuscript that has been accepted for publication in the European Respiratory Journal, prior to copy-editing, formatting and typesetting. This version of the manuscript may not be duplicated or reproduced without prior permission from the copyright owner, the European Respiratory Society. The publisher is not responsible or liable for any errors or omissions in this version of the manuscript or in any version derived from it by any other parties. The final, copy-edited, published article, which is the version of record, is available without a subscription 18 months after the date of issue publication. https://erj.ersjournals.com/content/early/2019/03/27/13993003.00457-2019 10.1183/13993003.00457-2019
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The Disconnected Mind Phase 3
Cox, S. (Principal Investigator) & Deary, I. (Co-investigator)
1/04/16 → 31/03/23
Project: Research
RA2665 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2.
Wardlaw, J. (Principal Investigator)
1/09/13 → 31/08/19
Project: Research

Data from: Epigenome-wide association study of lung function level and its change
Imboden, M. (Creator), Wielscher, M. (Creator), Rezwan, F. I. (Creator), Amaral, A. F. S. (Creator), Schaffner, E. (Creator), Jeong, A. (Creator), Beckmeyer-Borowko, A. (Creator), Harris, S. E. (Creator), Starr, J. M. (Creator), Deary, I. J. (Creator), Flexeder, C. (Creator), Waldenberger, M. (Creator), Peters, A. (Creator), Schulz, H. (Creator), Chen, S. (Creator), Sunny, S. K. (Creator), Karmaus, W. J. J. (Creator), Jiang, Y. (Creator), Erhart, G. (Creator), Kronenberg, F. (Creator), Arathimos, R. (Creator), Sharp, G. C. (Creator), Henderson, A. J. (Creator), Fu, Y. (Creator), Piirila, P. (Creator), Pietilainen, K. H. (Creator), Ollikainen, M. (Creator), Johannson, A. (Creator), Gyllensten, U. (Creator), De Vries, M. (Creator), Van Der Plaat, D. (Creator), De Jong, K. (Creator), Boezen, H. M. (Creator), Hall, I. P. (Creator), Tobin, M. D. (Creator), Järvelin, M.-R. (Creator), Holloway, J. W. (Creator), Jarvis, D. (Creator) & Probst-Hensch, N. M. (Creator), Dryad, 6 Jun 2019
DOI: 10.5061/dryad.pr10c20, https://zenodo.org/records/4963130
Dataset

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Imboden, M., Wielscher, M., Rezwan, F. I., Amaral, A. F. S., Schaffner, E., Jeong, A., Beckmeyer-Borowko, A., Harris, S., Starr, J., Deary, I., Flexeder, C., Waldenberger, M., Peters, A., Schulz, H., Chen, S., Shadia Khan, S., Karmaus, W. J. J., Jiang, Y., Erhart, G., ... Probst-Hensch, N. M. (2019). Epigenome-wide association study of lung function level and its change. European Respiratory Journal, 53(5). Advance online publication. https://doi.org/10.1183/13993003.00457-2019

@article{95f45578119d47f8992ef2725ee93d20,

title = "Epigenome-wide association study of lung function level and its change",

abstract = "Previous reports link differential DNA methylation (DNAme) to environmental exposures which are associated with lung function. Direct evidence on lung function DNAme is however limited. We undertook an agnostic epigenome-wide association study (EWAS) on pre-bronchodilation lung function and its change in adults.In a discovery-replication EWAS design, DNAme in blood and spirometry were measured twice, six-to-15 years apart, in the same participants of three adult population-based discovery cohorts (n=2,043). Associated DNAme markers (P<5x10-7) were tested in seven replication cohorts (adult: n=3,327; childhood: n=420). Technical-bias adjusted residuals of a regression of the normalized absolute beta-values on control-probe-derived principle components were regressed on level and change of FEV1, FEV1/FVC and FVC in covariate-adjusted discovery EWAS. Inverse-variance weighted meta-analyses were performed on results from discovery and replication samples in all participants and never smokers.EWAS signals were enriched for smoking-related DNAme. We replicated 57 lung function DNAme in adult, but not childhood samples, all previously associated with smoking. Markers not previously associated with smoking failed replication. cg05575921 (AHRR) showed the statistically most significant association with cross-sectional lung function (FEV1/FVC: Pdiscovery=3.96x10-21 and Pcombined=7.22x10-50). A score combining ten DNAme markers previously reported to mediate the smoking effect on lung function was associated with lung function (FEV1/FVC: P=2.65x10-20).Our results reveal that lung function associated methylation signals in adults are predominantly smoking-related and possibly of clinical utility in identifying poor lung function and accelerated decline. Larger studies with more repeat time points are needed to identify lung function DNAme in never smokers and in children.",

author = "Medea Imboden and Matthias Wielscher and Rezwan, \{Faisal I\} and Amaral, \{Andr{\'e} F S\} and Emmanuel Schaffner and Ayoung Jeong and Anna Beckmeyer-Borowko and Sarah Harris and John Starr and Ian Deary and Claudia Flexeder and Melanie Waldenberger and Annette Peters and Holger Schulz and Su Chen and \{Shadia Khan\}, Sunny and Karmaus, \{Wilifred J. J.\} and Yu Jiang and Gertraud Erhart and Florian Kronenberg and Ryan Arathimos and Sharp, \{Gemma C\} and Henderson, \{Alexander John\} and Yu Fu and P{\"a}ivi Piiril{\"a} and Pietil{\"a}inen, \{Kirsi H\} and M Ollikainen and Asa Johansson and Ulf Gyllensten and \{de Vries\}, Maaike and \{van der Plaat\}, \{Diana A.\} and \{de Jong\}, Kim and Boezen, \{H. Marike\} and Hall, \{Ian P.\} and Tobin, \{Martin D\} and Marjo-Riitta Jarvelin and Holloway, \{John W\} and Jarvis, \{Deborah L.\} and Probst-Hensch, \{Nicole M\}",

year = "2019",

month = may,

day = "9",

doi = "10.1183/13993003.00457-2019",

language = "English",

volume = "53",

journal = "European Respiratory Journal",

issn = "0903-1936",

publisher = "European Respiratory Society",

number = "5",

}

Imboden, M, Wielscher, M, Rezwan, FI, Amaral, AFS, Schaffner, E, Jeong, A, Beckmeyer-Borowko, A, Harris, S, Starr, J, Deary, I, Flexeder, C, Waldenberger, M, Peters, A, Schulz, H, Chen, S, Shadia Khan, S, Karmaus, WJJ, Jiang, Y, Erhart, G, Kronenberg, F, Arathimos, R, Sharp, GC, Henderson, AJ, Fu, Y, Piirilä, P, Pietiläinen, KH, Ollikainen, M, Johansson, A, Gyllensten, U, de Vries, M, van der Plaat, DA, de Jong, K, Boezen, HM, Hall, IP, Tobin, MD, Jarvelin, M-R, Holloway, JW, Jarvis, DL & Probst-Hensch, NM 2019, 'Epigenome-wide association study of lung function level and its change', European Respiratory Journal, vol. 53, no. 5. https://doi.org/10.1183/13993003.00457-2019

TY - JOUR

T1 - Epigenome-wide association study of lung function level and its change

AU - Imboden, Medea

AU - Wielscher, Matthias

AU - Rezwan, Faisal I

AU - Amaral, André F S

AU - Schaffner, Emmanuel

AU - Jeong, Ayoung

AU - Beckmeyer-Borowko, Anna

AU - Harris, Sarah

AU - Starr, John

AU - Deary, Ian

AU - Flexeder, Claudia

AU - Waldenberger, Melanie

AU - Peters, Annette

AU - Schulz, Holger

AU - Chen, Su

AU - Shadia Khan, Sunny

AU - Karmaus, Wilifred J. J.

AU - Jiang, Yu

AU - Erhart, Gertraud

AU - Kronenberg, Florian

AU - Arathimos, Ryan

AU - Sharp, Gemma C

AU - Henderson, Alexander John

AU - Fu, Yu

AU - Piirilä, Päivi

AU - Pietiläinen, Kirsi H

AU - Ollikainen, M

AU - Johansson, Asa

AU - Gyllensten, Ulf

AU - de Vries, Maaike

AU - van der Plaat, Diana A.

AU - de Jong, Kim

AU - Boezen, H. Marike

AU - Hall, Ian P.

AU - Tobin, Martin D

AU - Jarvelin, Marjo-Riitta

AU - Holloway, John W

AU - Jarvis, Deborah L.

AU - Probst-Hensch, Nicole M

PY - 2019/5/9

Y1 - 2019/5/9

N2 - Previous reports link differential DNA methylation (DNAme) to environmental exposures which are associated with lung function. Direct evidence on lung function DNAme is however limited. We undertook an agnostic epigenome-wide association study (EWAS) on pre-bronchodilation lung function and its change in adults.In a discovery-replication EWAS design, DNAme in blood and spirometry were measured twice, six-to-15 years apart, in the same participants of three adult population-based discovery cohorts (n=2,043). Associated DNAme markers (P<5x10-7) were tested in seven replication cohorts (adult: n=3,327; childhood: n=420). Technical-bias adjusted residuals of a regression of the normalized absolute beta-values on control-probe-derived principle components were regressed on level and change of FEV1, FEV1/FVC and FVC in covariate-adjusted discovery EWAS. Inverse-variance weighted meta-analyses were performed on results from discovery and replication samples in all participants and never smokers.EWAS signals were enriched for smoking-related DNAme. We replicated 57 lung function DNAme in adult, but not childhood samples, all previously associated with smoking. Markers not previously associated with smoking failed replication. cg05575921 (AHRR) showed the statistically most significant association with cross-sectional lung function (FEV1/FVC: Pdiscovery=3.96x10-21 and Pcombined=7.22x10-50). A score combining ten DNAme markers previously reported to mediate the smoking effect on lung function was associated with lung function (FEV1/FVC: P=2.65x10-20).Our results reveal that lung function associated methylation signals in adults are predominantly smoking-related and possibly of clinical utility in identifying poor lung function and accelerated decline. Larger studies with more repeat time points are needed to identify lung function DNAme in never smokers and in children.

AB - Previous reports link differential DNA methylation (DNAme) to environmental exposures which are associated with lung function. Direct evidence on lung function DNAme is however limited. We undertook an agnostic epigenome-wide association study (EWAS) on pre-bronchodilation lung function and its change in adults.In a discovery-replication EWAS design, DNAme in blood and spirometry were measured twice, six-to-15 years apart, in the same participants of three adult population-based discovery cohorts (n=2,043). Associated DNAme markers (P<5x10-7) were tested in seven replication cohorts (adult: n=3,327; childhood: n=420). Technical-bias adjusted residuals of a regression of the normalized absolute beta-values on control-probe-derived principle components were regressed on level and change of FEV1, FEV1/FVC and FVC in covariate-adjusted discovery EWAS. Inverse-variance weighted meta-analyses were performed on results from discovery and replication samples in all participants and never smokers.EWAS signals were enriched for smoking-related DNAme. We replicated 57 lung function DNAme in adult, but not childhood samples, all previously associated with smoking. Markers not previously associated with smoking failed replication. cg05575921 (AHRR) showed the statistically most significant association with cross-sectional lung function (FEV1/FVC: Pdiscovery=3.96x10-21 and Pcombined=7.22x10-50). A score combining ten DNAme markers previously reported to mediate the smoking effect on lung function was associated with lung function (FEV1/FVC: P=2.65x10-20).Our results reveal that lung function associated methylation signals in adults are predominantly smoking-related and possibly of clinical utility in identifying poor lung function and accelerated decline. Larger studies with more repeat time points are needed to identify lung function DNAme in never smokers and in children.

U2 - 10.1183/13993003.00457-2019

DO - 10.1183/13993003.00457-2019

M3 - Article

SN - 0903-1936

VL - 53

JO - European Respiratory Journal

JF - European Respiratory Journal

IS - 5

ER -

Epigenome-wide association study of lung function level and its change

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Projects

The Disconnected Mind Phase 3

RA2665 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2.

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Data from: Epigenome-wide association study of lung function level and its change

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