Genetic control of gene expression at novel and established chronic obstructive pulmonary disease loci

Peter J. Castaldi, Michael H. Cho, Xiaobo Zhou, Weiliang Qiu, Michael Mcgeachie, Bartolome Celli, Per Bakke, Amund Gulsvik, David A. Lomas, James D. Crapo, Terri H. Beaty, Stephen Rennard, Benjamin Harshfield, Christoph Lange, Dave Singh, Ruth Tal-singer, John H. Riley, John Quackenbush, Benjamin A. Raby, Vincent J. CareyEdwin K. Silverman, Craig P. Hersh

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Genetic risk loci have been identified for a wide range of diseases through genome-wide association studies (GWAS), but the relevant functional mechanisms have been identified for only a small proportion of these GWAS-identified loci. By integrating results from the largest current GWAS of chronic obstructive disease (COPD) with expression quantitative trait locus (eQTL) analysis in whole blood and sputum from 121 subjects with COPD from the ECLIPSE Study, this analysis identifies loci that are simultaneously associated with COPD and the expression of nearby genes (COPD eQTLs). After integrative analysis, 19 COPD eQTLs were identified, including all four previously identified genome-wide significant loci near HHIP, FAM13A, and the 15q25 and 19q13 loci. For each COPD eQTL, fine mapping and colocalization analysis to identify causal shared eQTL and GWAS variants identified a subset of sites with moderate-to-strong evidence of harboring at least one shared variant responsible for both the eQTL and GWAS signals. Transcription factor binding site (TFBS) analysis confirms that multiple COPD eQTL lead SNPs disrupt TFBS, and enhancer enrichment analysis for loci with the strongest colocalization signals showed enrichment for blood-related cell types (CD3 and CD4+ T cells, lymphoblastoid cell lines). In summary, integrative eQTL and GWAS analysis confirms that genetic control of gene expression plays a key role in the genetic architecture of COPD and identifies specific blood-related cell types as likely participants in the functional pathway from GWAS-associated variant to disease phenotype.

Original languageEnglish (US)
Pages (from-to)1200-1210
Number of pages11
JournalHuman Molecular Genetics
Volume24
Issue number4
DOIs
StatePublished - Feb 15 2015

Fingerprint

Genome-Wide Association Study
Chronic Obstructive Pulmonary Disease
Quantitative Trait Loci
Gene Expression
Blood Cells
Transcription Factors
Binding Sites
Genetic Loci
Sputum
Single Nucleotide Polymorphism
Chronic Disease
Genome
T-Lymphocytes
Phenotype
Cell Line

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Castaldi, P. J., Cho, M. H., Zhou, X., Qiu, W., Mcgeachie, M., Celli, B., ... Hersh, C. P. (2015). Genetic control of gene expression at novel and established chronic obstructive pulmonary disease loci. Human Molecular Genetics, 24(4), 1200-1210. https://doi.org/10.1093/hmg/ddu525

Genetic control of gene expression at novel and established chronic obstructive pulmonary disease loci. / Castaldi, Peter J.; Cho, Michael H.; Zhou, Xiaobo; Qiu, Weiliang; Mcgeachie, Michael; Celli, Bartolome; Bakke, Per; Gulsvik, Amund; Lomas, David A.; Crapo, James D.; Beaty, Terri H.; Rennard, Stephen; Harshfield, Benjamin; Lange, Christoph; Singh, Dave; Tal-singer, Ruth; Riley, John H.; Quackenbush, John; Raby, Benjamin A.; Carey, Vincent J.; Silverman, Edwin K.; Hersh, Craig P.

In: Human Molecular Genetics, Vol. 24, No. 4, 15.02.2015, p. 1200-1210.

Research output: Contribution to journalArticle

Castaldi, PJ, Cho, MH, Zhou, X, Qiu, W, Mcgeachie, M, Celli, B, Bakke, P, Gulsvik, A, Lomas, DA, Crapo, JD, Beaty, TH, Rennard, S, Harshfield, B, Lange, C, Singh, D, Tal-singer, R, Riley, JH, Quackenbush, J, Raby, BA, Carey, VJ, Silverman, EK & Hersh, CP 2015, 'Genetic control of gene expression at novel and established chronic obstructive pulmonary disease loci', Human Molecular Genetics, vol. 24, no. 4, pp. 1200-1210. https://doi.org/10.1093/hmg/ddu525
Castaldi, Peter J. ; Cho, Michael H. ; Zhou, Xiaobo ; Qiu, Weiliang ; Mcgeachie, Michael ; Celli, Bartolome ; Bakke, Per ; Gulsvik, Amund ; Lomas, David A. ; Crapo, James D. ; Beaty, Terri H. ; Rennard, Stephen ; Harshfield, Benjamin ; Lange, Christoph ; Singh, Dave ; Tal-singer, Ruth ; Riley, John H. ; Quackenbush, John ; Raby, Benjamin A. ; Carey, Vincent J. ; Silverman, Edwin K. ; Hersh, Craig P. / Genetic control of gene expression at novel and established chronic obstructive pulmonary disease loci. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 4. pp. 1200-1210.
@article{cfb549b388df47628166bfb76fa0aa4b,
title = "Genetic control of gene expression at novel and established chronic obstructive pulmonary disease loci",
abstract = "Genetic risk loci have been identified for a wide range of diseases through genome-wide association studies (GWAS), but the relevant functional mechanisms have been identified for only a small proportion of these GWAS-identified loci. By integrating results from the largest current GWAS of chronic obstructive disease (COPD) with expression quantitative trait locus (eQTL) analysis in whole blood and sputum from 121 subjects with COPD from the ECLIPSE Study, this analysis identifies loci that are simultaneously associated with COPD and the expression of nearby genes (COPD eQTLs). After integrative analysis, 19 COPD eQTLs were identified, including all four previously identified genome-wide significant loci near HHIP, FAM13A, and the 15q25 and 19q13 loci. For each COPD eQTL, fine mapping and colocalization analysis to identify causal shared eQTL and GWAS variants identified a subset of sites with moderate-to-strong evidence of harboring at least one shared variant responsible for both the eQTL and GWAS signals. Transcription factor binding site (TFBS) analysis confirms that multiple COPD eQTL lead SNPs disrupt TFBS, and enhancer enrichment analysis for loci with the strongest colocalization signals showed enrichment for blood-related cell types (CD3 and CD4+ T cells, lymphoblastoid cell lines). In summary, integrative eQTL and GWAS analysis confirms that genetic control of gene expression plays a key role in the genetic architecture of COPD and identifies specific blood-related cell types as likely participants in the functional pathway from GWAS-associated variant to disease phenotype.",
author = "Castaldi, {Peter J.} and Cho, {Michael H.} and Xiaobo Zhou and Weiliang Qiu and Michael Mcgeachie and Bartolome Celli and Per Bakke and Amund Gulsvik and Lomas, {David A.} and Crapo, {James D.} and Beaty, {Terri H.} and Stephen Rennard and Benjamin Harshfield and Christoph Lange and Dave Singh and Ruth Tal-singer and Riley, {John H.} and John Quackenbush and Raby, {Benjamin A.} and Carey, {Vincent J.} and Silverman, {Edwin K.} and Hersh, {Craig P.}",
year = "2015",
month = "2",
day = "15",
doi = "10.1093/hmg/ddu525",
language = "English (US)",
volume = "24",
pages = "1200--1210",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "4",

}

TY - JOUR

T1 - Genetic control of gene expression at novel and established chronic obstructive pulmonary disease loci

AU - Castaldi, Peter J.

AU - Cho, Michael H.

AU - Zhou, Xiaobo

AU - Qiu, Weiliang

AU - Mcgeachie, Michael

AU - Celli, Bartolome

AU - Bakke, Per

AU - Gulsvik, Amund

AU - Lomas, David A.

AU - Crapo, James D.

AU - Beaty, Terri H.

AU - Rennard, Stephen

AU - Harshfield, Benjamin

AU - Lange, Christoph

AU - Singh, Dave

AU - Tal-singer, Ruth

AU - Riley, John H.

AU - Quackenbush, John

AU - Raby, Benjamin A.

AU - Carey, Vincent J.

AU - Silverman, Edwin K.

AU - Hersh, Craig P.

PY - 2015/2/15

Y1 - 2015/2/15

N2 - Genetic risk loci have been identified for a wide range of diseases through genome-wide association studies (GWAS), but the relevant functional mechanisms have been identified for only a small proportion of these GWAS-identified loci. By integrating results from the largest current GWAS of chronic obstructive disease (COPD) with expression quantitative trait locus (eQTL) analysis in whole blood and sputum from 121 subjects with COPD from the ECLIPSE Study, this analysis identifies loci that are simultaneously associated with COPD and the expression of nearby genes (COPD eQTLs). After integrative analysis, 19 COPD eQTLs were identified, including all four previously identified genome-wide significant loci near HHIP, FAM13A, and the 15q25 and 19q13 loci. For each COPD eQTL, fine mapping and colocalization analysis to identify causal shared eQTL and GWAS variants identified a subset of sites with moderate-to-strong evidence of harboring at least one shared variant responsible for both the eQTL and GWAS signals. Transcription factor binding site (TFBS) analysis confirms that multiple COPD eQTL lead SNPs disrupt TFBS, and enhancer enrichment analysis for loci with the strongest colocalization signals showed enrichment for blood-related cell types (CD3 and CD4+ T cells, lymphoblastoid cell lines). In summary, integrative eQTL and GWAS analysis confirms that genetic control of gene expression plays a key role in the genetic architecture of COPD and identifies specific blood-related cell types as likely participants in the functional pathway from GWAS-associated variant to disease phenotype.

AB - Genetic risk loci have been identified for a wide range of diseases through genome-wide association studies (GWAS), but the relevant functional mechanisms have been identified for only a small proportion of these GWAS-identified loci. By integrating results from the largest current GWAS of chronic obstructive disease (COPD) with expression quantitative trait locus (eQTL) analysis in whole blood and sputum from 121 subjects with COPD from the ECLIPSE Study, this analysis identifies loci that are simultaneously associated with COPD and the expression of nearby genes (COPD eQTLs). After integrative analysis, 19 COPD eQTLs were identified, including all four previously identified genome-wide significant loci near HHIP, FAM13A, and the 15q25 and 19q13 loci. For each COPD eQTL, fine mapping and colocalization analysis to identify causal shared eQTL and GWAS variants identified a subset of sites with moderate-to-strong evidence of harboring at least one shared variant responsible for both the eQTL and GWAS signals. Transcription factor binding site (TFBS) analysis confirms that multiple COPD eQTL lead SNPs disrupt TFBS, and enhancer enrichment analysis for loci with the strongest colocalization signals showed enrichment for blood-related cell types (CD3 and CD4+ T cells, lymphoblastoid cell lines). In summary, integrative eQTL and GWAS analysis confirms that genetic control of gene expression plays a key role in the genetic architecture of COPD and identifies specific blood-related cell types as likely participants in the functional pathway from GWAS-associated variant to disease phenotype.

UR - http://www.scopus.com/inward/record.url?scp=84922438551&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84922438551&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddu525

DO - 10.1093/hmg/ddu525

M3 - Article

C2 - 25315895

AN - SCOPUS:84922438551

VL - 24

SP - 1200

EP - 1210

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 4

ER -