Title

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

Authors

Medea Imboden, Universitat Basel
Matthias Wielscher, Imperial College London
Faisal I. Rezwan, University of Southampton, Faculty of Medicine
André F.S. Amaral, Imperial College London
Emmanuel Schaffner, Swiss Tropical and Public Health Institute (Swiss TPH)
Ayoung Jeong, Swiss Tropical and Public Health Institute (Swiss TPH)
Anna Beckmeyer-Borowko, Swiss Tropical and Public Health Institute (Swiss TPH)
Sarah E. Harris, The University of Edinburgh
John M. Starr, The University of Edinburgh
Ian J. Deary, The University of Edinburgh
Claudia Flexeder, Helmholtz Center Munich German Research Center for Environmental Health
Melanie Waldenberger, Helmholtz Center Munich German Research Center for Environmental Health
Annette Peters, Helmholtz Center Munich German Research Center for Environmental Health
Holger Schulz, Helmholtz Center Munich German Research Center for Environmental Health
Su Chen, University of Memphis
Shadia Khan Sunny, University of Memphis
Wilfried J.J. Karmaus, University of Memphis
Yu Jiang, University of Memphis
Gertraud Erhart, Medizinische Universitat Innsbruck
Florian Kronenberg, Medizinische Universitat Innsbruck
Ryan Arathimos, University of Bristol
Gemma C. Sharp, University of Bristol
Alexander John Henderson, Bristol Medical School
Yu Fu, Helsingin Yliopisto
Päivi Piirilä, Helsinki University Hospital
Kirsi H. Pietiläinen, Helsingin Yliopisto
Miina Ollikainen, Helsingin Yliopisto
Asa Johansson, Uppsala Universitet
Ulf Gyllensten, Uppsala Universitet
Maaike De Vries, Universitair Medisch Centrum Groningen
Diana A. Van Der Plaat, Universitair Medisch Centrum Groningen
Kim De Jong, Universitair Medisch Centrum Groningen
H. Marike Boezen, Universitair Medisch Centrum Groningen

Abstract

Previous reports link differential DNA methylation (DNAme) to environmental exposures that 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, 6–15 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 β-values on control probe-derived principle components were regressed on level and change of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and their ratio (FEV1/FVC) in the 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 markers in adult, but not childhood samples, all previously associated with smoking. Markers not previously associated with smoking failed replication. cg05575921 (AHRR (aryl hydrocarbon receptor repressor)) 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 10 DNAme markers previously reported to mediate the effect of smoking 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.

Publication Title

European Respiratory Journal

Share

COinS