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 KronenbergRyan 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

Research output: Contribution to journalArticlepeer-review

49 Citations (Scopus)

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.

Original languageEnglish
Article number1900457
JournalThe European Respiratory Journal
Volume54
Issue number1
DOIs
Publication statusPublished - 31 Jul 2019
Externally publishedYes

Keywords

  • Adult
  • Aged
  • CpG Islands
  • DNA Methylation
  • Epigenesis, Genetic
  • Female
  • Forced Expiratory Volume
  • Genome-Wide Association Study
  • Humans
  • Linear Models
  • Male
  • Mendelian Randomization Analysis
  • Middle Aged
  • Reference Values
  • Smoking/genetics
  • Spirometry

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