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, 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

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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=2,043). Associated DNAme markers (P<5x10-7) were tested in seven replication cohorts (adult: n=3,327; childhood: n=420). Technical-bias adjusted residuals of a regression of the normalized 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=3.96x10-21 and Pcombined=7.22x10-50). A score combining ten DNAme markers previously reported to mediate the smoking effect on lung function was associated with lung function (FEV1/FVC: P=2.65x10-20). 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
Number of pages109
JournalEuropean Respiratory Journal
Issue number1
Early online date9 May 2019
Publication statusPublished - Jul 2019

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