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 journalArticlepeer-review

35 Scopus citations


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
Issue number4
StatePublished - Feb 15 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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