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Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

ABSTRACT: BACKGROUND:Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS:We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS:The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P ?=? 5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ?3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P ?=? 2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS:In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.

SUBMITTER: Tang W

PROVIDER: S-EPMC4077649 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

Tang Wenbo W Kowgier Matthew M Loth Daan W DW Soler Artigas María M Joubert Bonnie R BR Hodge Emily E Gharib Sina A SA Smith Albert V AV Ruczinski Ingo I Gudnason Vilmundur V Mathias Rasika A RA Harris Tamara B TB Hansel Nadia N NN Launer Lenore J LJ Barnes Kathleen C KC Hansen Joyanna G JG Albrecht Eva E Aldrich Melinda C MC Allerhand Michael M Barr R Graham RG Brusselle Guy G GG Couper David J DJ Curjuric Ivan I Davies Gail G Deary Ian J IJ Dupuis Josée J Fall Tove T Foy Millennia M Franceschini Nora N Gao Wei W Gläser Sven S Gu Xiangjun X Hancock Dana B DB Heinrich Joachim J Hofman Albert A Imboden Medea M Ingelsson Erik E James Alan A Karrasch Stefan S Koch Beate B Kritchevsky Stephen B SB Kumar Ashish A Lahousse Lies L Li Guo G Lind Lars L Lindgren Cecilia C Liu Yongmei Y Lohman Kurt K Lumley Thomas T McArdle Wendy L WL Meibohm Bernd B Morris Andrew P AP Morrison Alanna C AC Musk Bill B North Kari E KE Palmer Lyle J LJ Probst-Hensch Nicole M NM Psaty Bruce M BM Rivadeneira Fernando F Rotter Jerome I JI Schulz Holger H Smith Lewis J LJ Sood Akshay A Starr John M JM Strachan David P DP Teumer Alexander A Uitterlinden André G AG Völzke Henry H Voorman Arend A Wain Louise V LV Wells Martin T MT Wilk Jemma B JB Williams O Dale OD Heckbert Susan R SR Stricker Bruno H BH London Stephanie J SJ Fornage Myriam M Tobin Martin D MD O'Connor George T GT Hall Ian P IP Cassano Patricia A PA

PloS one 20140701 7

<h4>Background</h4>Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.<h4>Methods</h4>We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed ...[more]

PMID: 24983941

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Project description: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.

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Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

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Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

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