Open AccessPulmonary Function and Blood DNA Methylation: A Multiancestry Epigenome-Wide Association Meta-analysis
Author(s) -
Mi Kyeong 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 Smilnak,
Jessica Shaw,
Chen Xi Yang,
Elena Colicino,
Thanh T. Hoang,
Mairead Lesley Bermingham,
Hanfei Xu,
Anne E. Justice,
ChengJian Xu,
Stephen S. Rich,
Simon R. Cox,
Judith M. Vonk,
Ivana Prokić,
a Sotoodehnia,
Pei-Chien Tsai,
Joel 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 Vokonas,
Riccardo E. Marioni,
Adele M. Taylor,
Yongmei Liu,
R. Graham Barr,
Leslie A. Lange,
Andrea A. Baccarelli,
Ma’en Obeidat,
Myriam Fornage,
Tianyuan Wang,
James M. Ward,
Alison A. MotsingerReif,
Gibran Hemani,
Gerard H. Koppelman,
Jordana T. Bell,
Sina A. Gharib,
Guy Brusselle,
H. Marike Boezen,
Kari E. North,
Daniel Levy,
Kathryn Evans,
Josée Dupuis,
Charles E. Breeze,
Ani Manichaikul,
Stephanie J. London
Publication year - 2022
Publication title -
american journal of respiratory and critical care medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.272
H-Index - 374
eISSN - 1535-4970
pISSN - 1073-449X
DOI - 10.1164/rccm.202108-1907oc
Subject(s) - dna methylation , epigenome , epigenomics , genome wide association study , genetics , medicine , epigenetics , genetic association , bioinformatics , biology , gene , single nucleotide polymorphism , genotype , gene expression
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.