Panther results for biological processes.

<p>For each of the salmon, red, greenyellow, and black module, the top 10 enriched biological processes GO terms are presented. The reference list consists of the 6322 genes that were mapped by PANTHER and were common to all data sets and used for module construction. The # Hits denotes the number of genes in the module that are in the GO term. Fold Enrichment gives the overrepresentation. The <i>p</i>-values were calculated by the PANTHER software based on the binomial distribution. They were adjusted based on the Benjamini-Hochberg procedure on a per module basis, considering all tests for biological processes and molecular function (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0185682#pone.0185682.s012" target="_blank">S2 Table</a> for molecular function GO term results).</p

Top 10 module membership genes.

<p>The module membership of a gene (kME) is the correlation between the gene and the eigengene of the module. For the black, salmon, red and greenyellow modules, we list the top 10 kME genes based on the sum of ranks in the COPDGene and ECLIPSE cohort. The ranks were based on kME. For COPDGene and ECLIPSE, the correlation direction between the gene and the phenotypes are represented by “+” and “-”, if the correlation is significant at <i>α</i> = 0.05.</p

Demographics.

<p>Demographics.</p

Correspondence of individual and consensus modules.

<p>Left (right, respectively) panel shows the correspondence between consensus modules and COPDGene (ECLIPSE, respectively) modules. The row labels give the color (label) of the consensus modules and the number of genes in the module. The columns represent in an analogous way the modules for COPDGene and ECLIPSE. The number in each cell gives the number of genes common to the modules in the corresponding row and column; the heatmap colors represent the −log₁₀ transformed <i>p</i>-values (truncated at 50), which are based on Fisher’s exact test based on the hypergeometric distribution. Note that the module colors have no meaning, they simply represent consensus modules or modules in the individual data sets.</p

Consensus module-trait relationships across COPDGene, ECLIPSE, and TESRA for cases only.

<p><i>Z</i>-scores and meta <i>p</i>-values for FEV₁% and FEV₁/FVC were based on COPDGene, ECLIPSE, and TESRA cases. The meta <i>p</i>-value for emphysema was based on COPDGene and ECLIPSE only, since the definition of emphysema in TESRA differed (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0185682#sec002" target="_blank">Materials and methods</a>). As in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0185682#pone.0185682.g002" target="_blank">Fig 2</a>, the relationship information is given in terms of <i>Z</i>-scores rather than correlations.</p

Overrepresentation of cell-type specific genes in modules.

<p>Only overrepresentations significant at level <i>α</i> = 0.05 are displayed for readability. For a complete table of <i>p</i>-values, see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0185682#pone.0185682.s013" target="_blank">S3 Table</a>. The 11 groups of distinct immune cell types considered consist of eosinophils (eos), basophils/mast cells (mast_baso), dendritic cells (dendr), neutrophils (neut), b-cells, t-cells, NK-cells, t-helper cells (thelp), monocyte Lipopolysaccharides (LPS) day 0 stimulation, monocyte LPS day 1 stimulation, monocyte LPS day 7 stimulation (mono_d0, mono_d1, mono_d7, respectively).</p

Consensus module−trait relationships across COPDGene and ECLIPSE for cases and controls.

<p>Meta-analysis <i>Z</i>-scores and <i>p</i>-values were based on cases and controls from COPDGene and ECLIPSE. The sign and magnitude of the <i>Z</i>-score give information about the overall direction and magnitude of association.</p

DNA methylation profiling in human lung tissue identifies genes associated with COPD

<p>Chronic obstructive pulmonary disease (COPD) is a smoking-related disease characterized by genetic and phenotypic heterogeneity. Although association studies have identified multiple genomic regions with replicated associations to COPD, genetic variation only partially explains the susceptibility to lung disease, and suggests the relevance of epigenetic investigations. We performed genome-wide DNA methylation profiling in homogenized lung tissue samples from 46 control subjects with normal lung function and 114 subjects with COPD, all former smokers. The differentially methylated loci were integrated with previous genome-wide association study results. The top 535 differentially methylated sites, filtered for a minimum mean methylation difference of 5% between cases and controls, were enriched for CpG shelves and shores. Pathway analysis revealed enrichment for transcription factors. The top differentially methylated sites from the intersection with previous GWAS were in <i>CHRM1, GLT1D1</i>, and <i>C10orf11</i>; sorted by GWAS <i>P</i>-value, the top sites included <i>FRMD4A, THSD4</i>, and <i>C10orf11</i>. Epigenetic association studies complement genetic association studies to identify genes potentially involved in COPD pathogenesis. Enrichment for genes implicated in asthma and lung function and for transcription factors suggests the potential pathogenic relevance of genes identified through differential methylation and the intersection with a broader range of GWAS associations.</p