Paired parallel boxplots of DNA methylation level versus case-control status for the 4 unique top 1 CpG sites obtained by the 7 equal-variance tests based on GSE37020.

<p>The red dots indicate subjects. 2a1, 2b1, 2c1 are for cg26363196 (F), cg00027083 (Levene), and cg06675478 (BF), respectively, based on GSE37020; 2a2 2b2, 2c2 are for cg26363196 (F), cg00027083 (Levene), and cg06675478 (BF), respectively, based on GSE20080.</p

Plots of <i>n</i>_{<i>reject</i>} versus <i>m</i>, where <i>n</i>_{<i>reject</i>} is the number of scenarios where an equal-variance test rejected the null hypothesis <i>H</i>_<i>0</i> that the type I error rates is ≤ 0.05 and <i>m</i> is the median of the ranks of powers.

<p>For ranks with ties, average ranks were used. The upper-left, upper-right, bottom-left panels are the plots where <i>n</i>_{<i>reject</i>} and <i>m</i> were obtained based on scenarios with sample size 20, 50, or 200 subjects per group, respectively. The bottom-right panel is the plot where <i>n</i>_{<i>reject</i>} and <i>m</i> were obtained based on all 48 scenarios.</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

Areas Under the Curve (AUCs) for discrimination of comorbidity scores with regards to primary outcome SGRQ.

<p>All three scores compared to “empty” model (including age, gender, race, FEV1, pack-years smoked and current smoking status). ROC for empty model is 0.7393.</p

Mean, SD and adjusted associations of comorbidity scores and SGRQ value using COPDGene.

<p>Coefficients adjusted for age, race, FEV1, pack-years smoked, current smoking status and gender.</p><p>Equation for weighted comorbidity score: (4·93*coronary heart disease) + (4·69*diabetes) + (6·53*congestive heart failure) + (5·96*stroke) + (5·13*osteoarthritis) + (4·31*osteoporosis) + (3·24*hypertension) + (2·14*high cholesterol) + (6·45*GERD) + (4·94*stomach ulcers) + (5*obesity) + (8·83*sleep apnea) + (2·75*hay fever) + (3·71*peripheral vascular disease).</p><p>Equation for weighted score based on backwards selection: (2·16*coronary heart disease) + (1·39*diabetes) + (2·37*congestive heart failure) + (4·71*stroke) + (2·35*osteoarthritis) + (3·29*osteoporosis) + (0·89*hypertension) + (4·13*GERD) + (2·48*stomach ulcers) + (2·69*obesity) + (6·49*sleep apnea) + (1·20*hay fever).</p><p>Mean, SD and adjusted associations of comorbidity scores and SGRQ value using COPDGene.</p

Characteristics of participants with COPD based upon number of comorbidities.

<p>All values as mean(SD) unless otherwise indicated.</p><p>Characteristics of participants with COPD based upon number of comorbidities.</p

Discrimination measures (AUC) and calibration measures (Hosmer-Lemeshow calibration statistics) for comorbidity count with regards to outcomes of exacerbations, MMRC, and 6MWD, in the SPIROMICS participants.

<p>Above models also include terms for age, gender, race, baseline FEV1, pack-years smoked and current smoking status. Every score above added to “empty” model, with addition of score improving AUC significantly (p<0·001 for all comparisons). The AUCs for the empty models are as follows: SGRQ 0.7741, Exacerbations 0.7223, MMRC 0.7499, 6MWD 0.6970. For associations with outcome, OR for exacerbations represents risk for exacerbation conferred by one point increase in comorbidity score, OR for MMRC represents risk for worse dyspnea score conferred by one point increase in comorbidity score, and β's for SGRQ and 6MWD represent decrement in health status and exercise capacity conferred by one point increase in comorbidity score. All ROCs estimated using logistic regression with outcomes of SGRQ (group mean 35.4, SD 18.9), MMRC (group mean 1.18, SD 0.99) and 6MWD (group mean 395.5, SD 112.5) dichotomized at group mean.</p><p>Discrimination measures (AUC) and calibration measures (Hosmer-Lemeshow calibration statistics) for comorbidity count with regards to outcomes of exacerbations, MMRC, and 6MWD, in the SPIROMICS participants.</p

Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts

Background: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes.Methods: We constructed a polygenic risk score using a genome wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC Findings: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74–1·88] and non-European (1·42 [1·34–1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56–9·72) in European ancestry and 4·83 (3·45–6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79–0·81] vs 0·76 [0·75 0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern. Interpretation: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth.</div

Top regions of association in mouse and human.

<p>Mouse plots near (A) <i>Kcnip4</i> and (B) <i>Pdzd2/Golph3/Mtmr12/Zfr</i> contain –Log₁₀ of EMMA p-values vs. position along the corresponding mouse chromosome. Corresponding human homologous plots near (C) <i>KCNIP4</i> and (D) <i>PDZD2/GOLPH3/MTMR12/ZFR</i>. The x-axis denotes position along corresponding human chromosome, while the y-axis denotes –Log₁₀(P) corresponding to EVE p-values for the combined sample GWAS (C) or European American GWAS (D). LD between the SNPs with the lowest P-value to other SNPs in the human plots are denoted in colors and were computed according to HapMap Phase 2 CEU data using LocusZoom <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056179#pone.0056179-Pruim1" target="_blank">[55]</a>.</p

Effect Sizes of Top <i>KCNIP4</i> SNP Associations.

<p>Odds ratios are shown for asthma (EVE combined cohort, GABRIEL, Sepracor/LOCCS/LODO/Illumina (SLLI), and DAG) and for AHR (SHARP AHR for change in LnPC20, DAG AHR for change in Ln(Slope)). EVE, GABRIEL, and SHARP include 95% confidence intervals. SLLI includes standard errors.</p