Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function
Creators: name: Tang, Wenbo
name: Kowgier, Matthew
name: Loth, Daan W.
name: Artigas, María Soler
name: Joubert, Bonnie R.
name: Hodge, Emily
name: Gharib, Sina A.
name: Smith, Albert V.
name: Ruczinski, Ingo
name: Gudnason, Vilmundur
name: Mathias, Rasika A.
name: Hansel, Nadia N.
name: Harris, Tamara B.
name: Barnes, Kathleen C.
name: Albrecht, Eva
name: Launer, Lenore J.
name: Hansen, Joyanna G.
name: Aldrich, Melinda C.
name: Allerhand, Michael
name: Barr, R. Graham
name: Brusselle, Guy G.
name: Curjuric, Ivan
name: Davies, Gail
name: Couper, David J.
name: Deary, Ian J.
name: Dupuis, Josée
name: Foy, Millennia
name: Franceschini, Nora
name: Fall, Tove
name: Gao, Wei
name: Gläser, Sven
name: Gu, Xiangjun
name: Hancock, Dana B.
name: Heinrich, Joachim
name: Hofman, Albert
name: Imboden, Medea
name: Ingelsson, Erik
name: James, Alan
name: Karrasch, Stefan
name: Koch, Beate
name: Kritchevsky, Stephen B.
name: Kumar, Ashish
name: Li, Guo
name: Lahousse, Lies
name: Lind, Lars
name: Liu, Yongmei
name: Lindgren, Cecilia
name: Lohman, Kurt
name: Lumley, Thomas
name: McArdle, Wendy L.
name: Meibohm, Bernd
name: Morris, Andrew P.
name: Morrison, Alanna C.
name: Musk, Bill
name: North, Kari E.
name: Palmer, Lyle J.
name: Probst-Hensch, Nicole M.
name: Psaty, Bruce M.
name: Rivadeneira, Fernando
name: Rotter, Jerome I.
name: Schulz, Holger
name: Sood, Akshay
name: Smith, Lewis J.
name: Starr, John M.
name: Uitterlinden, André G.
name: Strachan, David P.
name: Teumer, Alexander
name: Voorman, Arend
name: Völzke, Henry
name: Wain, Louise V.
name: Wells, Martin T.
name: Williams, O. Dale
name: Wilk, Jemma B.
name: Heckbert, Susan R.
name: Stricker, Bruno H.
name: London, Stephanie J.
name: Fornage, Myriam
name: Tobin, Martin D.
name: O′Connor, George T.
name: Cassano, Patricia A.
name: Hall, Ian P.
Publisher: name: Columbia University
Year: 2014
Subjects: subject: Lungs
subject: Gene expression
subject: Genomics
subject: Genetics
subject: FOS: Biological sciences

description: 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.