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 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.


CONCLUSIONS
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.
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.
Tsung-Chieh
TC
Yao
Department of Human Genetics, University of Chicago, Chicago, Ill.
Gaixin
G
Du
Department of Human Genetics, University of Chicago, Chicago, Ill.
Lide
L
Han
Department of Human Genetics, University of Chicago, Chicago, Ill.
Ying
Y
Sun
Department of Medicine, University of California, San Francisco, Calif.
Donglei
D
Hu
Department of Public Health Sciences, Henry Ford Health System, Detroit, Mich.
James J
JJ
Yang
Division of Allergy and Clinical Immunology, Department of Medicine, The Johns Hopkins University, Baltimore, Md.
Rasika
R
Mathias
Department of Medicine, University of California, San Francisco, Calif.
Lindsey A
LA
Roth
Division of Allergy and Clinical Immunology, Department of Medicine, The Johns Hopkins University, Baltimore, Md.
Nicholas
N
Rafaels
Department of Human Genetics, University of Chicago, Chicago, Ill.
Emma E
EE
Thompson
Department of Human Genetics, University of Chicago, Chicago, Ill.
Dagan A
DA
Loisel
Department of Human Genetics, University of Chicago, Chicago, Ill.
Rebecca
R
Anderson
Department of Medicine, University of California, San Francisco, Calif.
Celeste
C
Eng
Department of Human Genetics, University of Chicago, Chicago, Ill.
Maitane
M
Arruabarrena Orbegozo
Department of Pediatrics, University of Chicago, Chicago, Ill.
Melody
M
Young
Department of Medicine, University of Chicago, Chicago, Ill.
James M
JM
Klocksieben
Department of Pediatrics, University of Wisconsin, Madison, Wis.
Elizabeth
E
Anderson
Department of Pediatrics, University of Wisconsin, Madison, Wis.
Kathleen
K
Shanovich
Department of Pediatrics, University of Chicago, Chicago, Ill.
Lucille A
LA
Lester
Center for Health Services Research and Department of Internal Medicine, Henry Ford Health System, Detroit, Mich.
L Keoki
LK
Williams
Division of Allergy and Clinical Immunology, Department of Medicine, The Johns Hopkins University, Baltimore, Md.
Kathleen C
KC
Barnes
Department of Medicine, University of California, San Francisco, Calif; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, Calif.
Esteban G
EG
Burchard
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.
Dan L
DL
Nicolae
Department of Human Genetics, University of Chicago, Chicago, Ill.
Mark
M
Abney
Department of Human Genetics, University of Chicago, Chicago, Ill. Electronic address: c-ober@genetics.uchicago.edu.
Carole
C
Ober
D000293:Adolescent; D000328:Adult; D000368:Aged; D054377:Chemokine CXCL12 / Q000235:genetics*; D019742:Chemokines, CC / Q000235:genetics*; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D018928:Immunity, Mucosal / Q000235:genetics; D008168:Lung / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012119:Respiration / Q000235:genetics* / Q000276:immunology; D012129:Respiratory Function Tests; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics*; D014481:United States; D055815:Young Adult; D023083:beta-Defensins / Q000235:genetics*
C111792:CCL18 protein, human; D054377:Chemokine CXCL12; D019742:Chemokines, CC; C108467:TNFRSF13B protein, human; D053303:Transmembrane Activator and CAML Interactor Protein; D023083:beta-Defensins
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