Human Lung DNA Methylation Quantitative Trait Loci Colocalize with Chronic Obstructive Pulmonary Disease Genome-Wide Association Loci

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, g...

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Bibliographic Details
Published in:American journal of respiratory and critical care medicine 2018-05, Vol.197 (10), p.1275-1284
Main Authors: Morrow, Jarrett D, Glass, Kimberly, Cho, Michael H, Hersh, Craig P, Pinto-Plata, Victor, Celli, Bartolome, Marchetti, Nathaniel, Criner, Gerard, Bueno, Raphael, Washko, George, Choi, Augustine M K, Quackenbush, John, Silverman, Edwin K, DeMeo, Dawn L
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Chronic obstructive pulmonary disease
DNA methylation
DNA Methylation - genetics
Epigenetics
Epigenomics
Female
Gene Expression Regulation
Gene loci
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Lung - physiopathology
Male
Middle Aged
Original
Pulmonary Disease, Chronic Obstructive - epidemiology
Pulmonary Disease, Chronic Obstructive - genetics
Quantitative Trait Loci
United States - epidemiology
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Summary: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. 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. 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. 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 
ISSN:1073-449X
1535-4970
DOI:10.1164/rccm.201707-1434OC