posted on 2019-10-02, 09:33authored byM Imboden, M Wielscher, FI Rezwan, AFS Amaral, E Schaffner, A Jeong, A Beckmeyer-Borowko, SE Harris, JM Starr, IJ Deary, C Flexeder, M Waldenberger, A Peters, H Schulz, S Chen, SK Sunny, WJJ Karmaus, Y Jiang, G Erhart, F Kronenberg, R Arathimos, GC Sharp, AJ Henderson, Y Fu, P Piirilä, KH Pietiläinen, M Ollikainen, A Johansson, U Gyllensten, M de Vries, DA van der Plaat, K de Jong, HM Boezen, IP Hall, MD Tobin, M-R Jarvelin, JW Holloway, D Jarvis, NM Probst-Hensch
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.
Funding
This work has been conducted within the Aging Lungs in European Cohorts (ALEC) project, funded from the European Union's Horizon 2020 research and innovation programme under grant agreement 633212. The funding agency had no role in the design, data collection and analysis of the data. Cohort-specific funding details are provided in the supplementary material. Funding information for this article has been deposited with the Crossref Funder Registry.
History
Citation
European Respiratory Journal, 2019, 54: 1900457;
Author affiliation
/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Health Sciences
Statistical codes and full discovery/replication EWAS effect estimates (meta-analysed and cohort-specific)
are made publically available with no end date on the public repository DRYAD (http://datadryad.org/) at
the time of publication. Access restrictions apply to the individual methylome data underlying the analysis.
Contact details for data requests to the contributing cohorts can be found in the supplementary material http://erj.ersjournals.com/lookup/doi/10.1183/13993003.00457-2019.figures-only#fig-data-supplementary-materials