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. 2015 Feb 15;24(4):1200-10.
doi: 10.1093/hmg/ddu525. Epub 2014 Oct 14.

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

Peter J Castaldi  1 , Michael H Cho  2 , Xiaobo Zhou  2 , Weiliang Qiu  3 , Michael Mcgeachie  3 , Bartolome Celli  4 , Per Bakke  5 , Amund Gulsvik  5 , David A Lomas  6 , James D Crapo  7 , Terri H Beaty  8 , Stephen Rennard  9 , Benjamin Harshfield  3 , Christoph Lange  10 , Dave Singh  11 , Ruth Tal-Singer  12 , John H Riley  13 , John Quackenbush  14 , Benjamin A Raby  2 , Vincent J Carey  3 , Edwin K Silverman  2 , Craig P Hersh  2
Affiliations

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

Peter J Castaldi et al. Hum Mol Genet. .

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.

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Figures

Figure 1.
Figure 1.
Locus Plots for COPD GWAS and whole-blood eQTL association near HHIP. COPD GWAS association results are shown in (A) whole-blood eQTL association is shown in (B) and COPD association conditioned on lead eQTL SNP rs12504628 demonstrates complete attenuation of the association signal (C).
Figure 2.
Figure 2.
Lead GWAS and eQTL SNPs in the 15q25 region. Locus plots for association with COPD susceptibility (A) and showing only the lead GWAS SNP (diamond) and lead eQTL SNPs (circles) for four probesets mapping to IREB2, CHRNA3 and PSMA4 (B). Linkage disequilibrium plot with R2 values for the lead GWAS and lead eQTLs SNPs (C).
Figure 3.
Figure 3.
Locus plots for conditional association with COPD susceptibility in the 15q25 Locus. Association results conditioning on lead eQTL rs10519203 (A) and lead eQTL rs1062980 (B) attenuate different components of the overall association signal, and conditioning on both lead eQTL SNPs simultaneously completely attenuates the association (C).
Figure 4.
Figure 4.
Locus plots for COPD GWAS and whole-blood eQTL association near USP34. COPD GWAS association results are shown in (A) whole-blood eQTL Association is shown on (B) and COPD association conditioned on lead eQTL SNP rs2600671 demonstrates complete attenuation of the association signal (C).
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