Pulmonary Function and Blood DNA Methylation: A Multiancestry Epigenome-Wide Association Meta-analysis

Abstract

Rationale Methylation integrates factors present at birth and modifiable across the lifespan that can influence pulmonary function. Studies are limited in scope and replication. Objectives To conduct large-scale epigenome-wide meta-analyses of blood DNA methylation and pulmonary function. Methods Twelve cohorts analyzed associations of methylation at cytosine-phosphate-guanine probes (CpGs), using Illumina 450K or EPIC/850K arrays, with FEV 1 , FVC, and FEV 1 /FVC. We performed multiancestry epigenome-wide meta-analyses (total of 17,503 individuals; 14,761 European, 2,549 African, and 193 Hispanic/Latino ancestries) and interpreted results using integrative epigenomics. Measurements and Main Results We identified 1,267 CpGs (1,042 genes) differentially methylated (false discovery rate, <0.025) in relation to FEV 1 , FVC, or FEV 1 /FVC, including 1,240 novel and 73 also related to chronic obstructive pulmonary disease (1,787 cases). We found 294 CpGs unique to European or African ancestry and 395 CpGs unique to never or ever smokers. The majority of significant CpGs correlated with nearby gene expression in blood. Findings were enriched in key regulatory elements for gene function, including accessible chromatin elements, in both blood and lung. Sixty-nine implicated genes are targets of investigational or approved drugs. One example novel gene highlighted by integrative epigenomic and druggable target analysis is TNFRSF4. Mendelian randomization and colocalization analyses suggest that epigenome-wide association study signals capture causal regulatory genomic loci. Conclusions We identified numerous novel loci differentially methylated in relation to pulmonary function; few were detected in large genome-wide association studies. Integrative analyses highlight functional relevance and potential therapeutic targets. This comprehensive discovery of potentially modifiable, novel lung function loci expands knowledge gained from genetic studies, providing insights into lung pathogenesis.

The relationship between the epigenetic aging biomarker “grimage” and lung function in both the airway and blood of people living with HIV: An observational cohort study

“…DNA methylation changes also represent a molecular marker by which we can link aging with the environmental and genetic factors leading to COPD. 7 , 8 These properties of DNA methylation have been explored in the context of epigenetic clocks, which provide a compelling indication of biological age. 9 , 10 , 11 In the past, we have used DNA methylation to show that HIV is associated with epigenetic age acceleration compared to uninfected individuals 12 , 13 and that airflow obstruction is also associated with global hypomethylation in blood.…”

Plasticity of Individual Lung Function States from Childhood to Adulthood

“…), and validation in other ethnic groups and in other environmental contexts. In addition, our observations on related inflammatory biomarkers are needed to be validated in other populations, and other omics layers such as epigenetics need to be further explored ( 41 ). Large-scale collaboration involving multiple cohorts, such as the CADSET (Chronic Airway Disease Early Stratification) collaboration ( 42 ), would be needed for such analyses.…”

The complexity in DNA methylation analysis of allergic diseases

“…Over 300 loci have been previously associated with pulmonary function by large GWAS studies [10,11], and over 500 loci by several EWAS studies [12–15]. The largest so far ( n = 17 503) pulmonary function-related multiancestry EWAS meta-analysis, of blood from mainly European, but also African and Hispanic/Latino populations was conducted [16 ▪▪ ]. Overall, 1267 CpGs were differentially methylated, with 294 CpGs unique to European or African ancestry, and a majority related to gene expression.…”