TY - JOUR
T1 - Pulmonary Function and Blood DNA Methylation A Multiancestry Epigenome-Wide Association Meta-analysis
AU - Lee, Mikyeong
AU - Huan, Tianxiao
AU - McCartney, Daniel L.
AU - Chittoor, Geetha
AU - de Vries, Maaike
AU - Lahousse, Lies
AU - Nguyen, Jennifer N.
AU - Brody, Jennifer A.
AU - Castillo-Fernandez, Juan
AU - Terzikhan, Natalie
AU - Qi, Cancan
AU - Joehanes, Roby
AU - Min, Josine L.
AU - Smilnak, Gordon J.
AU - Shaw, Jessica R.
AU - Yang, Chen Xi
AU - Colicino, Elena
AU - Hoang, Thanh T.
AU - Bermingham, Mairead L.
AU - Xu, Hanfei
AU - Justice, Anne E.
AU - Xu, Cheng Jian
AU - Rich, Stephen S.
AU - Cox, Simon R.
AU - Vonk, Judith M.
AU - Prokic, Ivana
AU - Sotoodehnia, Nona
AU - Tsai, Pei Chien
AU - Schwartz, Joel D.
AU - Leung, Janice M.
AU - Sikdar, Sinjini
AU - Walker, Rosie M.
AU - Harris, Sarah E.
AU - van der Plaat, Diana A.
AU - Van Den Berg, David J.
AU - Bartz, Traci M.
AU - Spector, Tim D.
AU - Vokonas, Pantel S.
AU - Marioni, Riccardo E.
AU - Taylor, Adele M.
AU - Liu, Yongmei
AU - Barr, R. Graham
AU - Lange, Leslie A.
AU - Baccarelli, Andrea A.
AU - Obeidat, Maen
AU - Fornage, Myriam
AU - Wang, Tianyuan
AU - Ward, James M.
AU - Motsinger-Reif, Alison A.
AU - Hemani, Gibran
AU - Koppelman, Gerard H.
AU - Bell, Jordana T.
AU - Gharib, Sina A.
AU - Brusselle, Guy
AU - Boezen, H. Marike
AU - North, Kari E.
AU - Levy, Daniel
AU - Evans, Kathryn L.
AU - Dupuis, Josee
AU - Breeze, Charles E.
AU - Manichaikul, Ani
AU - London, Stephanie J.
N1 - 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.
PY - 2022/8/1
Y1 - 2022/8/1
N2 - 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.
AB - 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.
KW - chronic obstructive pulmonary disease
KW - epigenetics
KW - respiratory function tests
KW - spirometry
UR - http://www.scopus.com/inward/record.url?scp=85135398333&partnerID=8YFLogxK
U2 - 10.1164/rccm.202108-1907OC
DO - 10.1164/rccm.202108-1907OC
M3 - Article
C2 - 35536696
AN - SCOPUS:85135398333
VL - 206
SP - 321
EP - 336
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
SN - 1073-449X
IS - 3
ER -