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

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Mikyeong Lee, Tianxiao Huan, Daniel L. McCartney, Geetha Chittoor, Maaike de Vries, Lies Lahousse, Jennifer N. Nguyen, Jennifer A. Brody, Juan Castillo-Fernandez, Natalie Terzikhan, Cancan Qi, Roby Joehanes, Josine L. Min, Gordon J. Smilnak, Jessica R. Shaw, Chen Xi Yang, Elena Colicino, Thanh T. Hoang, Mairead L. Bermingham, Hanfei Xu & 42 more Anne E. Justice, Cheng Jian Xu, Stephen S. Rich, Simon R. Cox, Judith M. Vonk, Ivana Prokic, Nona Sotoodehnia, Pei Chien Tsai, Joel D. Schwartz, Janice M. Leung, Sinjini Sikdar, Rosie M. Walker, Sarah E. Harris, Diana A. van der Plaat, David J. Van Den Berg, Traci M. Bartz, Tim D. Spector, Pantel S. Vokonas, Riccardo E. Marioni, Adele M. Taylor, Yongmei Liu, R. Graham Barr, Leslie A. Lange, Andrea A. Baccarelli, Maen 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, Josee Dupuis, Charles E. Breeze, Ani Manichaikul, Stephanie J. London

Original languageEnglish
Pages (from-to)321-336
Number of pages16
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number3
Published1 Aug 2022

Bibliographical note

Funding Information: Supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01-ES043012). Infrastructure for the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium is supported in part by the National Heart, Lung, and Blood Institute (HL105756). Additional study-specific funding statements can be found in the online supplement. Publisher Copyright: © 2022 by the American Thoracic Society.

King's Authors


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.

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