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&lt;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.,statistical_codescontains the statistical codes used to: 1- derive residuals of methylation data ; 2a - run EWAS cross-sectionally; 2b - run EWAS as repeated cross-sectional analysis; 2c - run EWAS predictive association with change in outcome; 3a - meta-analysis script for replication ; 3b - combined discovery and replication meta-analysis script.DiscoveryResultsByCohorts_archive.tarThis archive contains all the cohort-specific discovery EWAS results. See read-me file for details.DiscoveryResultsByCohorts.tar.gzDiscoveryMetaResults_archive.tarThis archive contains all the discovery EWAS meta-analysed results. See read-me file for details.DiscoveryMetaResults.tar.gzReplicationResultsByCohorts.tarThis archive contains all the cohort-specific replication results. See read-me file for details.ReplicationMetaResults.tarThis archive contains all the replication meta-analysed results. See read-me file for details.CombinedMetaResults.tarThis archive contains the discovery cohort and replication cohort combined meta-analysed results. See read-me file for details.ChildhoodMetaResults.tarThis archive contains all the childhood cohort replication meta-analysed results. See read-me file for details.,</span
