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

Authors :
Lee M
Huan T
McCartney DL
Chittoor G
de Vries M
Lahousse L
Nguyen JN
Brody JA
Castillo-Fernandez J
Terzikhan N
Qi C
Joehanes R
Min JL
Smilnak GJ
Shaw JR
Yang CX
Colicino E
Hoang TT
Bermingham ML
Xu H
Justice AE
Xu CJ
Rich SS
Cox SR
Vonk JM
Prokić I
Sotoodehnia N
Tsai PC
Schwartz JD
Leung JM
Sikdar S
Walker RM
Harris SE
van der Plaat DA
Van Den Berg DJ
Bartz TM
Spector TD
Vokonas PS
Marioni RE
Taylor AM
Liu Y
Barr RG
Lange LA
Baccarelli AA
Obeidat M
Fornage M
Wang T
Ward JM
Motsinger-Reif AA
Hemani G
Koppelman GH
Bell JT
Gharib SA
Brusselle G
Boezen HM
North KE
Levy D
Evans KL
Dupuis J
Breeze CE
Manichaikul A
London SJ
Source :
American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2022 Aug 01; Vol. 206 (3), pp. 321-336.
Publication Year :
2022

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 <subscript>1</subscript> , FVC, and FEV <subscript>1</subscript> /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 <subscript>1</subscript> , FVC, or FEV <subscript>1</subscript> /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.

Details

Language :
English
ISSN :
1535-4970
Volume :
206
Issue :
3
Database :
MEDLINE
Journal :
American journal of respiratory and critical care medicine
Publication Type :
Academic Journal
Accession number :
35536696
Full Text :
https://doi.org/10.1164/rccm.202108-1907OC