Genome-wide association study of lung function phenotypes in a founder population

Background Lung function is a long-term predictor of mortality and morbidity. Objective We sought to identify single nucleotide polymorphisms (SNPs) associated with lung function. Methods We performed a genome-wide association study (GWAS) of FEV1 , forced vital capacity (FVC), and FEV1 /FVC in 1144...

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Published in:Journal of allergy and clinical immunology 2014-01, Vol.133 (1), p.248-255.e10
Main Authors: Yao, Tsung-Chieh, MD, PhD, Du, Gaixin, MS, Han, Lide, PhD, Sun, Ying, MS, Hu, Donglei, PhD, Yang, James J., PhD, Mathias, Rasika, ScD, Roth, Lindsey A., MA, Rafaels, Nicholas, MS, Thompson, Emma E., PhD, Loisel, Dagan A., PhD, Anderson, Rebecca, MS, Eng, Celeste, BS, Arruabarrena Orbegozo, Maitane, RN, Young, Melody, RN, Klocksieben, James M., BA, Anderson, Elizabeth, RN, Shanovich, Kathleen, MS, RN, Lester, Lucille A., MD, Williams, L. Keoki, MD, MPH, Barnes, Kathleen C., PhD, Burchard, Esteban G., MD, MPH, Nicolae, Dan L., PhD, Abney, Mark, PhD, Ober, Carole, PhD
Format: Article
Language:English
Subjects:
Adolescent
Adult
Aged
Allergy and Immunology
beta-Defensins - genetics
Biological and medical sciences
Chemokine CXCL12 - genetics
Chemokines, CC - genetics
Child
Colonies & territories
Female
FEV1
FEV1/FVC
Fundamental and applied biological sciences. Psychology
Fundamental immunology
FVC
Genetic Predisposition to Disease
Genome-Wide Association Study
Genomes
GRAIL
GWAS
Humans
Immunity, Mucosal - genetics
Immunopathology
LASSO regression
Lung - physiology
Male
Medical sciences
Middle Aged
Polymorphism, Single Nucleotide
Population
Respiration - genetics
Respiration - immunology
Respiratory Function Tests
Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis
Studies
Transmembrane Activator and CAML Interactor Protein - genetics
United States
Young Adult
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Summary:Background Lung function is a long-term predictor of mortality and morbidity. Objective We sought to identify single nucleotide polymorphisms (SNPs) associated with lung function. Methods We performed a genome-wide association study (GWAS) of FEV1 , forced vital capacity (FVC), and FEV1 /FVC in 1144 Hutterites aged 6 to 89 years, who are members of a founder population of European descent. We performed least absolute shrinkage and selection operation regression to select the minimum set of SNPs that best predict FEV1 /FVC in the Hutterites and used the GRAIL algorithm to mine the Gene Ontology database for evidence of functional connections between genes near the predictive SNPs. Results Our GWAS identified significant associations between FEV1 /FVC and SNPs at the THSD4-UACA-TLE3 locus on chromosome 15q23 ( P  = 5.7 × 10−8 to 3.4 × 10−9 ). Nine SNPs at or near 4 additional loci had P  < 10−5 with FEV1 /FVC. Only 2 SNPs were found with P  < 10−5 for FEV1 or FVC. We found nominal levels of significance with SNPs at 9 of the 27 previously reported loci associated with lung function measures. Among a predictive set of 80 SNPs, 6 loci were identified that had a significant degree of functional connectivity (GRAIL P  < .05), including 3 clusters of β-defensin genes, 2 chemokine genes ( CCL18 and CXCL12 ), and TNFRSF13B. Conclusion This study identifies genome-wide significant associations and replicates results of previous GWASs. Multimarker modeling implicated for the first time common variation in genes involved in antimicrobial immunity in airway mucosa that influences lung function.
ISSN:0091-6749
1097-6825
DOI:10.1016/j.jaci.2013.06.018