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J Allergy Clin Immunol. 2014 Jan;133(1):248-55.e1-10. doi: 10.1016/j.jaci.2013.06.018. Epub 2013 Aug 6.

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

Author information

1
Department of Human Genetics, University of Chicago, Chicago, Ill; Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan. Electronic address: yao@adm.cgmh.org.tw.
2
Department of Human Genetics, University of Chicago, Chicago, Ill.
3
Department of Medicine, University of California, San Francisco, Calif.
4
Department of Public Health Sciences, Henry Ford Health System, Detroit, Mich.
5
Division of Allergy and Clinical Immunology, Department of Medicine, The Johns Hopkins University, Baltimore, Md.
6
Department of Pediatrics, University of Chicago, Chicago, Ill.
7
Department of Medicine, University of Chicago, Chicago, Ill.
8
Department of Pediatrics, University of Wisconsin, Madison, Wis.
9
Center for Health Services Research and Department of Internal Medicine, Henry Ford Health System, Detroit, Mich.
10
Department of Medicine, University of California, San Francisco, Calif; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, Calif.
11
Department of Human Genetics, University of Chicago, Chicago, Ill; Department of Pediatrics, University of Chicago, Chicago, Ill; Department of Statistics, University of Chicago, Chicago, Ill.
12
Department of Human Genetics, University of Chicago, Chicago, Ill. Electronic address: c-ober@genetics.uchicago.edu.

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.

KEYWORDS:

COPD; Chronic obstructive pulmonary disease; FEV(1); FEV(1)/FVC; FVC; Forced vital capacity; GRAIL; GWAS; Genome-wide association study; LASSO; LASSO regression; Least absolute shrinkage and selection operation; SNP; Single nucleotide polymorphism

PMID:
23932459
PMCID:
PMC4270121
DOI:
10.1016/j.jaci.2013.06.018
[Indexed for MEDLINE]
Free PMC Article

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