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

Tsung Chieh Yao, Gaixin Du, Lide Han, Ying Sun, Donglei Hu, James J. Yang, Rasika Mathias, Lindsey A. Roth, Nicholas Rafaels, Emma E. Thompson, Dagan A. Loisel, Rebecca Anderson, Celeste Eng, Maitane Arruabarrena Orbegozo, Melody Young, James M. Klocksieben, Elizabeth Anderson, Kathleen Shanovich, Lucille A. Lester, L. Keoki WilliamsKathleen C. Barnes, Esteban G. Burchard, Dan L. Nicolae, Mark Abney, Carole Ober

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)248-255.e10
JournalJournal of Allergy and Clinical Immunology
Volume133
Issue number1
DOIs
StatePublished - Jan 2014

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Keywords

  • FVC
  • GRAIL
  • GWAS
  • LASSO regression

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Yao, T. C., Du, G., Han, L., Sun, Y., Hu, D., Yang, J. J., Mathias, R., Roth, L. A., Rafaels, N., Thompson, E. E., Loisel, D. A., Anderson, R., Eng, C., Arruabarrena Orbegozo, M., Young, M., Klocksieben, J. M., Anderson, E., Shanovich, K., Lester, L. A., ... Ober, C. (2014). Genome-wide association study of lung function phenotypes in a founder population. Journal of Allergy and Clinical Immunology, 133(1), 248-255.e10. https://doi.org/10.1016/j.jaci.2013.06.018