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

Chen, Lin and Tang, Wenbo and Kowgier, Matthew and Loth, Daan W. and Soler Artigas, María and Joubert, Bonnie R. and Hodge, Emily and Gharib, Sina A. and Smith, Albert V. and Ruczinski, Ingo and Gudnason, Vilmundur and Mathias, Rasika A. and Harris, Tamara B. and Hansel, Nadia N. and Launer, Lenore J. and Barnes, Kathleen C. and Hansen, Joyanna G. and Albrecht, Eva and Aldrich, Melinda C. and Allerhand, Michael and Barr, R. Graham and Brusselle, Guy G. and Couper, David J. and Curjuric, Ivan and Davies, Gail and Deary, Ian J. and Dupuis, Josée and Fall, Tove and Foy, Millennia and Franceschini, Nora and Gao, Wei and Gläser, Sven and Gu, Xiangjun and Hancock, Dana B. and Heinrich, Joachim and Hofman, Albert and Imboden, Medea and Ingelsson, Erik and James, Alan and Karrasch, Stefan and Koch, Beate and Kritchevsky, Stephen B. and Kumar, Ashish and Lahousse, Lies and Li, Guo and Lind, Lars and Lindgren, Cecilia and Liu, Yongmei and Lohman, Kurt and Lumley, Thomas and McArdle, Wendy L. and Meibohm, Bernd and Morris, Andrew P. and Morrison, Alanna C. and Musk, Bill and North, Kari E. and Palmer, Lyle J. and Probst-Hensch, Nicole M. and Psaty, Bruce M. and Rivadeneira, Fernando and Rotter, Jerome I. and Schulz, Holger and Smith, Lewis J. and Sood, Akshay and Starr, John M. and Strachan, David P. and Teumer, Alexander and Uitterlinden, André G. and Völzke, Henry and Voorman, Arend and Wain, Louise V. and Wells, Martin T. and Wilk, Jemma B. and Williams, O. Dale and Heckbert, Susan R. and Stricker, Bruno H. and London, Stephanie J. and Fornage, Myriam and Tobin, Martin D. and O′Connor, George T. and Hall, Ian P. and Cassano, Patricia A. (2014) Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function. PLoS ONE, 9 (7). e100776. ISSN 1932-6203

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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 6 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 = 2.18610-8) 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.

Item Type: Article
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine > Division of Respiratory Medicine
Identification Number: 10.1371/journal.pone.0100776
Depositing User: Eprints, Support
Date Deposited: 21 Jul 2017 11:12
Last Modified: 21 Jul 2017 22:00

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