Human lung DNA methylation quantitative trait loci colocalize with chronic obstructive pulmonary disease genome-Wide association loci

Jarrett D. Morrow, Kimberly Glass, Michael H. Cho, Craig P. Hersh, Victor Pinto-Plata, Bartolome Celli, Nathaniel Marchetti, Gerard Criner, Raphael Bueno, George Washko, Augustine M.K. Choi, John Quackenbush, Edwin K. Silverman, Dawn L. DeMeo

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Rationale: As the third leading cause of death in the United States, the impact of chronic obstructive pulmonary disease (COPD) makes identification of its molecular mechanisms of great importance. Genome-wide association studies (GWASs) have identified multiple genomic regions associated with COPD. However, genetic variation only explains a small fraction of the susceptibility to COPD, and sub–genome-wide significant loci may play a role in pathogenesis. Objectives: Regulatory annotation with epigenetic evidence may give priority for further investigation, particularly for GWAS associations in noncoding regions. We performed integrative genomics analyses using DNA methylation profiling and genome-wide SNP genotyping from lung tissue samples from 90 subjects with COPD and 36 control subjects. Methods: We performed methylation quantitative trait loci (mQTL) analyses, testing for SNPs associated with percent DNA methylation and assessed the colocalization of these results with previous COPD GWAS findings using Bayesian methods in the R package coloc to highlight potential regulatory features of the loci. Measurements and Main Results: We identified 942,068 unique SNPs and 33,996 unique CpG sites among the significant (5% false discovery rate) cis-mQTL results. The genome-wide significant and subthreshold (P, 10 24 ) GWAS SNPs were enriched in the significant mQTL SNPs (hypergeometric test P, 0.00001). We observed enrichment for sites located in CpG shores and shelves, but not CpG islands. Using Bayesian colocalization, we identified loci in regions near KCNK3, EEFSEC, PIK3CD, DCDC2C, TCERG1L, FRMD4B, and IL27. Conclusions: Colocalization of mQTL and GWAS loci provides regulatory characterization of significant and subthreshold GWAS findings, supporting a role for genetic control of methylation in COPD pathogenesis.

Original languageEnglish (US)
Pages (from-to)1275-1284
Number of pages10
JournalAmerican journal of respiratory and critical care medicine
Issue number10
StatePublished - May 15 2018


  • Chronic obstructive pulmonary disease
  • Epigenetics
  • MQTL
  • Methylation QTL

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine


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