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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 E. Harris, John M. Starr, Ian J. Deary, Claudia Flexeder, Melanie Waldenberger, Annette Peters, Holger Schulz, Su Chen, Shadia Khan Sunny, Wilfried J.J. Karmaus, Yu Jiang, Gertraud Erhart, Florian Kronenberg, Ryan Arathimos, Gemma C. Sharp, Alexander John Henderson, Yu Fu, Päivi Piirilä, Kirsi H. Pietiläinen, Miina 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 Jarvis, Nicole M. Probst-Hensch
European Respiratory Journal 2019; DOI: 10.1183/13993003.00457-2019
Medea Imboden
1Swiss Tropical and Public Health Institute, Basel, Switzerland
2University of Basel, Switzerland
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  • For correspondence: medea.imboden@swisstph.ch nicole.probst@swisstph.ch
Matthias Wielscher
3MRC-PHE Centre for Environment and Health, Imperial College London, London, UK
4Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
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Faisal I. Rezwan
5Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK
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André F.S. Amaral
3MRC-PHE Centre for Environment and Health, Imperial College London, London, UK
6Population Health and Occupational Disease, NHLI, Imperial College London, London, UK
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Emmanuel Schaffner
1Swiss Tropical and Public Health Institute, Basel, Switzerland
2University of Basel, Switzerland
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Ayoung Jeong
1Swiss Tropical and Public Health Institute, Basel, Switzerland
2University of Basel, Switzerland
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Anna Beckmeyer-Borowko
1Swiss Tropical and Public Health Institute, Basel, Switzerland
2University of Basel, Switzerland
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Sarah E. Harris
7Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
8Medical Genetics Section, University of Edinburgh Centre for Genomic and Experimental Medicine and MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK
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John M. Starr
7Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
9Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK
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Ian J. Deary
7Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
10Department of Psychology, University of Edinburgh, Edinburgh, UK
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Claudia Flexeder
11Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
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Melanie Waldenberger
11Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
12Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
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Annette Peters
11Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
12Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
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Holger Schulz
11Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
13Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL)
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Su Chen
14Department of Mathematical Sciences, University of Memphis, Memphis, TN, USA
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Shadia Khan Sunny
15Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA
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Wilfried J.J. Karmaus
15Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA
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Yu Jiang
15Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA
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Gertraud Erhart
16Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
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Florian Kronenberg
16Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
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Ryan Arathimos
17MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
18Department of Population Health Sciences, Bristol Medical School, University of Bristol, UK
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Gemma C. Sharp
17MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
18Department of Population Health Sciences, Bristol Medical School, University of Bristol, UK
19Bristol Dental School, University of Bristol, Bristol, UK
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Alexander John Henderson
18Department of Population Health Sciences, Bristol Medical School, University of Bristol, UK
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Yu Fu
20Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland
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Päivi Piirilä
21Unit of Clinical Physiology, HUS Medical Imaging Center, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
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Kirsi H. Pietiläinen
22Obesity Research Unit, Reserch Programs Unit, University of Helsinki, Helsinki, Finland
23Abdominal Center, Endocrinology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
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Miina Ollikainen
20Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland
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Asa Johansson
24Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden
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Ulf Gyllensten
24Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden
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Maaike de Vries
25University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, Netherlands
26Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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  • ORCID record for Maaike de Vries
Diana A. van der Plaat
25University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, Netherlands
26Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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Kim de Jong
25University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, Netherlands
26Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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H. Marike Boezen
25University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, Netherlands
26Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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Ian P. Hall
27Division of Respiratory Medicine, University of Nottingham, Nottingham, UK; National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals, Nottingham, UK
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Martin D. Tobin
28Department of Health Sciences, University of Leicester, Leicester, UK
29National Institute of Health Research Biomedical Research Centre, University of Leicester, Leicester, UK
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Marjo-Riitta Jarvelin
4Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
30Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Finland
31Biocenter Oulu, University of Oulu, Oulu, Finland
32Unit of Primary Health Care, Oulu University Hospital, Finland
33Department of Life Sciences, College of Health and Life Sciences, Brunel University London, UK
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John W. Holloway
5Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK
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Deborah Jarvis
3MRC-PHE Centre for Environment and Health, Imperial College London, London, UK
6Population Health and Occupational Disease, NHLI, Imperial College London, London, UK
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Nicole M. Probst-Hensch
1Swiss Tropical and Public Health Institute, Basel, Switzerland
2University of Basel, Switzerland
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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.

Footnotes

This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.

Conflict of interest: Dr. Imboden has nothing to disclose.

Conflict of interest: Dr. Wielscher has nothing to disclose.

Conflict of interest: Dr. Rezwan has nothing to disclose.

Conflict of interest: Dr. Amaral has nothing to disclose.

Conflict of interest: Dr. Schaffner has nothing to disclose.

Conflict of interest: Dr. Jeong has nothing to disclose.

Conflict of interest: Dr. Beckmeyer-Borowko has nothing to disclose.

Conflict of interest: Dr. Harris reports grants from Medical Research Council, grants from Biotechnology and Biological Sciences Research Council, grants from Age UK, grants from The Wellcome Trust, during the conduct of the study.

Conflict of interest: Dr. Starr has nothing to disclose.

Conflict of interest: Dr. Deary reports grants from Age UK, grants from Medical Research Council, during the conduct of the study.

Conflict of interest: Dr. Flexeder has nothing to disclose.

Conflict of interest: Dr. Waldenberger has nothing to disclose.

Conflict of interest: Dr. Peters has nothing to disclose.

Conflict of interest: Dr. Schulz reports grants from Competence Network Asthma and COPD (ASCONET), network COSYCONET, grants from Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research (DZL), during the conduct of the study.

Conflict of interest: Dr. CHEN has nothing to disclose.

Conflict of interest: Dr. Sunny has nothing to disclose.

Conflict of interest: Dr. Karmaus has nothing to disclose.

Conflict of interest: Dr. Jiang has nothing to disclose.

Conflict of interest: Erhart has nothing to disclose.

Conflict of interest: Dr. Kronenberg has nothing to disclose.

Conflict of interest: Dr. Arathimos has nothing to disclose.

Conflict of interest: Dr. Sharp has nothing to disclose.

Conflict of interest: Dr. Henderson reports grants from Medical Research Council, grants from Wellcome Trust, during the conduct of the study.

Conflict of interest: Dr. Fu has nothing to disclose.

Conflict of interest: Päivi Piirilä has no conflicts of interests to the manuscript of Medea Imboden et al.

Conflict of interest: Dr. Pietiläinen has nothing to disclose.

Conflict of interest: Dr. Ollikainen has nothing to disclose.

Conflict of interest: Dr. Johansson has nothing to disclose.

Conflict of interest: Dr. Gyllensten has nothing to disclose.

Conflict of interest: Dr. de Vries has nothing to disclose.

Conflict of interest: Dr. van der Plaat has nothing to disclose.

Conflict of interest: Dr. de Jong has nothing to disclose.

Conflict of interest: Dr. Boezen has nothing to disclose.

Conflict of interest: Dr. Hall reports grants from GSK, grants from Boehringer Ingelheim, outside the submitted work.

Conflict of interest: Dr. Tobin reports grants from Research collaboration with Pfizer, grants from Research collaboration with GSK, outside the submitted work.

Conflict of interest: Dr. Jarvelin has nothing to disclose.

Conflict of interest: Dr. Holloway reports grants from European Union, grants from National Institutes of Health, during the conduct of the study.

Conflict of interest: Prof. Jarvis reports grants from EU, grants from Medical research council, grants from Asthma UK, during the conduct of the study.

Conflict of interest: Dr. Probst-Hensch has nothing to disclose.

This is a PDF-only article. Please click on the PDF link above to read it.

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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 E. Harris, John M. Starr, Ian J. Deary, Claudia Flexeder, Melanie Waldenberger, Annette Peters, Holger Schulz, Su Chen, Shadia Khan Sunny, Wilfried J.J. Karmaus, Yu Jiang, Gertraud Erhart, Florian Kronenberg, Ryan Arathimos, Gemma C. Sharp, Alexander John Henderson, Yu Fu, Päivi Piirilä, Kirsi H. Pietiläinen, Miina 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 Jarvis, Nicole M. Probst-Hensch
European Respiratory Journal Jan 2019, 1900457; DOI: 10.1183/13993003.00457-2019

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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 E. Harris, John M. Starr, Ian J. Deary, Claudia Flexeder, Melanie Waldenberger, Annette Peters, Holger Schulz, Su Chen, Shadia Khan Sunny, Wilfried J.J. Karmaus, Yu Jiang, Gertraud Erhart, Florian Kronenberg, Ryan Arathimos, Gemma C. Sharp, Alexander John Henderson, Yu Fu, Päivi Piirilä, Kirsi H. Pietiläinen, Miina 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 Jarvis, Nicole M. Probst-Hensch
European Respiratory Journal Jan 2019, 1900457; DOI: 10.1183/13993003.00457-2019
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