Pulmonary Function and Blood DNA Methylation: A Multiancestry Epigenome-Wide Association Meta-analysis
Mi Kyeong Lee, Tianxiao Huan, Daniel L. McCartney, Geetha Chittoor, Maaike de Vries, Lies Lahousse, Jennifer Nguyen, Jennifer A. Brody, Juan Castillo‐Fernandez, Natalie Terzikhan, Cancan Qi, Roby Joehanes, Josine L. Min, Gordon Smilnak, Jessica R. Shaw, Chen Xi Yang, Elena Colicino, Thanh T. Hoang, Mairead L. Bermingham, Hanfei Xu, Anne E. Justice, Cheng‐Jian Xu, Stephen S. Rich, Simon R. Cox, Judith M. Vonk, Ivana Nedeljković, Nona Sotoodehnia, Pei-Chien Tsai, Joel Schwartz, Janice M. Leung, Sinjini Sikdar, Rosie M. Walker, Sarah E. Harris, Diana A. van der Plaat, David Van Den Berg, Traci M. Bartz, Tim D. Spector, Pantel Vokonas, Riccardo E. Marioni, Adele Taylor, Yongmei Liu, R. Graham Barr, Leslie A. Lange, Andrea Baccarelli, Ma’en Obeidat, Myriam Fornage, Tianyuan Wang, James M. Ward, Alison A. Motsinger‐Reif, Gibran Hemani, Gerard H. Koppelman, Jordana T. Bell, Sina A. Gharib, Guy Brusselle, H. Marike Boezen, Kari E. North, Daniel Levy, Kathryn L. Evans, Josée Dupuis, Charles E. Breeze, Ani Manichaikul, Stephanie J. London
Abstract
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 FEV1, FVC, and FEV1/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 FEV1, FVC, or FEV1/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.