Human Lung DNA Methylation Quantitative Trait Loci Colocalize with COPD Genome-wide Association Loci.

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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 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.


Regulatory annotation with epigenetic evidence may give priority for further investigation, particularly for GWAS associations in non-coding 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 controls.


We performed methylation QTL (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.


We identified 942,068 unique SNPs and 33,996 unique CpG sites among the significant (5% FDR) cis-mQTL results. The genome-wide significant and sub-threshold (p<10-4) 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.


Colocalization of methylation QTL and GWAS loci provides regulatory characterization of significant and sub-threshold GWAS findings, supporting a role for genetic control of methylation in COPD pathogenesis.

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