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 Williams; Kathleen C. Barnes; Esteban G. Burchard; Dan L. Nicolae; Mark Abney; Carole Ober

doi:10.1016/j.jaci.2013.06.018

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

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 language	English (US)
Pages (from-to)	248-255.e10
Journal	Journal of Allergy and Clinical Immunology
Volume	133
Issue number	1
DOIs	https://doi.org/10.1016/j.jaci.2013.06.018
State	Published - Jan 2014

Keywords

FVC
GRAIL
GWAS
LASSO regression

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1016/j.jaci.2013.06.018

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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

Yao, TC, Du, G, Han, L, Sun, Y, Hu, D, Yang, JJ, Mathias, R, Roth, LA, Rafaels, N, Thompson, EE, Loisel, DA, Anderson, R, Eng, C, Arruabarrena Orbegozo, M, Young, M, Klocksieben, JM, Anderson, E, Shanovich, K, Lester, LA, Williams, LK, Barnes, KC, Burchard, EG, Nicolae, DL, Abney, M & Ober, C 2014, 'Genome-wide association study of lung function phenotypes in a founder population', Journal of Allergy and Clinical Immunology, vol. 133, no. 1, pp. 248-255.e10. https://doi.org/10.1016/j.jaci.2013.06.018

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title = "Genome-wide association study of lung function phenotypes in a founder population",

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 = "FVC, GRAIL, GWAS, LASSO regression",

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

note = "Funding Information: Supported by the National Institutes of Health grant R01 HL085197 (C.O.) and grant R01 HG002899 (M.A.). Funding Information: Disclosure of potential conflict of interest: L. Han, J. J. Yang, R. Mathais, E. E. Thompson, D. A. Loisel, R. Anderson, M. A. Orbegozo, M. Young, J. M. Klocksieben, L. A. Lester, K. C. Barnes, M. Abney, and C. Ober have received grants from the National Institutes of Health (NIH) . C. Eng has received grants from the NIH and the National Heart Lung and Blood Institute . L. K. Williams has received grants from the NIH , the National Institute of Allergy and Infectious Disease, and the National Institute of Diabetes and Digestive and Kidney Diseases , and has received payment for lectures from Merck & Company. E. G. Burchard has received grants from the NIH and the National Heart Lung and Blood Institute . The rest of the authors declare that they have no relevant conflicts of interest. ",

year = "2014",

month = jan,

doi = "10.1016/j.jaci.2013.06.018",

language = "English (US)",

volume = "133",

pages = "248--255.e10",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "1",

}

TY - JOUR

T1 - Genome-wide association study of lung function phenotypes in a founder population

AU - Yao, Tsung Chieh

AU - Du, Gaixin

AU - Han, Lide

AU - Sun, Ying

AU - Hu, Donglei

AU - Yang, James J.

AU - Mathias, Rasika

AU - Roth, Lindsey A.

AU - Rafaels, Nicholas

AU - Thompson, Emma E.

AU - Loisel, Dagan A.

AU - Anderson, Rebecca

AU - Eng, Celeste

AU - Arruabarrena Orbegozo, Maitane

AU - Young, Melody

AU - Klocksieben, James M.

AU - Anderson, Elizabeth

AU - Shanovich, Kathleen

AU - Lester, Lucille A.

AU - Williams, L. Keoki

AU - Barnes, Kathleen C.

AU - Burchard, Esteban G.

AU - Nicolae, Dan L.

AU - Abney, Mark

AU - Ober, Carole

N1 - Funding Information: Supported by the National Institutes of Health grant R01 HL085197 (C.O.) and grant R01 HG002899 (M.A.). Funding Information: Disclosure of potential conflict of interest: L. Han, J. J. Yang, R. Mathais, E. E. Thompson, D. A. Loisel, R. Anderson, M. A. Orbegozo, M. Young, J. M. Klocksieben, L. A. Lester, K. C. Barnes, M. Abney, and C. Ober have received grants from the National Institutes of Health (NIH) . C. Eng has received grants from the NIH and the National Heart Lung and Blood Institute . L. K. Williams has received grants from the NIH , the National Institute of Allergy and Infectious Disease, and the National Institute of Diabetes and Digestive and Kidney Diseases , and has received payment for lectures from Merck & Company. E. G. Burchard has received grants from the NIH and the National Heart Lung and Blood Institute . The rest of the authors declare that they have no relevant conflicts of interest.

PY - 2014/1

Y1 - 2014/1

N2 - 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.

AB - 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.

KW - FVC

KW - GRAIL

KW - GWAS

KW - LASSO regression

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

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