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

Epigenome-wide association study of lung function level and its change
Epigenome-wide association study of lung function level and its change
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=2043). Associated DNAme markers (p<5×10−7) were tested in seven replication cohorts (adult: n=3327; childhood: n=420). Technical-bias adjusted residuals of a regression of the normalised 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=3.96×10−21 and Pcombined=7.22×10−50). A score combining ten DNAme markers previously reported to mediate the smoking effect on lung function was associated with lung function (FEV1/FVC: p=2.65×10−20).

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.
0903-1936
Imboden, Medea
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Schulz, Holger
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Karmaus, Wilfried J.J.
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Jiang, Yu
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Erhart, Gertraud
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Henderson, Alexander John
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Fu, Yu
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Piirila, Paivi
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Pietiläinen, Kirsi H.
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Ollikainen, Miina
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Gyllensten, Ulf
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de Vries, Maaike
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van der Plaat, Diana A.
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de Jong, Kim
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Hall, Ian P.
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Tobin, Martin D.
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Jarvelin, Marjo-Riitta
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Holloway, John
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Jarvis, Deborah
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Probst-Hensch, Nicole M.
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Imboden, Medea
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Wielscher, Matthias
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Rezwan, Faisal I.
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Amaral, André F.S.
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Schaffner, Emmanuel
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Jeong, Ayoung
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Beckmeyer-Borowko, Anna
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Harris, Sarah E.
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Starr, John M.
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Deary, Ian J.
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Flexeder, Claudia
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Chen, Su
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Sunny, Shadia Khan
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Karmaus, Wilfried J.J.
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Jiang, Yu
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Erhart, Gertraud
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Kronenberg, Florian
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Arathimos, Ryan
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Sharp, Gemma C.
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Henderson, Alexander John
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Fu, Yu
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Piirila, Paivi
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Pietiläinen, Kirsi H.
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Ollikainen, Miina
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Gyllensten, Ulf
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de Vries, Maaike
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van der Plaat, Diana A.
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de Jong, Kim
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Boezen, H. Marike
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Hall, Ian P.
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Tobin, Martin D.
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Jarvelin, Marjo-Riitta
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Holloway, John
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Jarvis, Deborah
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Probst-Hensch, Nicole M.
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Imboden, Medea, Wielscher, Matthias, Rezwan, Faisal I., Amaral, André F.S., Schaffner, Emmanuel, Jeong, Ayoung, Beckmeyer-Borowko, Anna, Harris, Sarah E., Starr, John M., Deary, Ian J., Flexeder, Claudia, Waldenberger, Melanie, Peters, Annette, Schulz, Holger, Chen, Su, Sunny, Shadia Khan, Karmaus, Wilfried J.J., Jiang, Yu, Erhart, Gertraud, Kronenberg, Florian, Arathimos, Ryan, Sharp, Gemma C., Henderson, Alexander John, Fu, Yu, Piirila, Paivi, Pietiläinen, Kirsi H., Ollikainen, Miina, Johansson, Åsa, Gyllensten, Ulf, de Vries, Maaike, van der Plaat, Diana A., de Jong, Kim, Boezen, H. Marike, Hall, Ian P., Tobin, Martin D., Jarvelin, Marjo-Riitta, Holloway, John, Jarvis, Deborah and Probst-Hensch, Nicole M. (2019) Epigenome-wide association study of lung function level and its change. European Respiratory Journal, 54 (1), [1900457]. (doi:10.1183/13993003.00457-2019).

Record type: Article

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=2043). Associated DNAme markers (p<5×10−7) were tested in seven replication cohorts (adult: n=3327; childhood: n=420). Technical-bias adjusted residuals of a regression of the normalised 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=3.96×10−21 and Pcombined=7.22×10−50). A score combining ten DNAme markers previously reported to mediate the smoking effect on lung function was associated with lung function (FEV1/FVC: p=2.65×10−20).

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.

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Main text tables figures EWAS LuFu ALEC final revision - Accepted Manuscript
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Additional Tables Imbodenetal - Accepted Manuscript
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Supplement EWAS LuFu ALEC final - Accepted Manuscript
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More information

Accepted/In Press date: 27 March 2019
e-pub ahead of print date: 4 July 2019
Published date: 4 July 2019
Related URLs:
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Identifiers

Local EPrints ID: 430619
URI: http://eprints.soton.ac.uk/id/eprint/430619
DOI: doi:10.1183/13993003.00457-2019
ISSN: 0903-1936
PURE UUID: 09e645fc-59be-49be-9287-b577626bee61
ORCID for Faisal I. Rezwan: ORCID iD orcid.org/0000-0001-9921-222X
ORCID for John Holloway: ORCID iD orcid.org/0000-0001-9998-0464

Catalogue record

Date deposited: 07 May 2019 16:30
Last modified: 16 Mar 2024 07:49

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Contributors

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

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