Pulmonary Function and Blood DNA Methylation: A Multi-Ancestry Epigenome-Wide Association Meta-Analysis

BIOS consortium, GoDMC; 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; Anne E Justice; Cheng-Jian Xu; Stephen S Rich; Simon R Cox; Judith M Vonk; Ivana Prokić; 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; Ma'en Obeidat; Myriam Fornage; Tianyuan Wang; James M Ward; Gerard H Koppelman; H Marike Boezen; Stephanie J London

doi:10.1164/rccm.202108-1907OC

Pulmonary Function and Blood DNA Methylation: A Multi-Ancestry Epigenome-Wide Association Meta-Analysis

BIOS consortium, GoDMC, 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 BerminghamHanfei Xu, Anne E Justice, Cheng-Jian Xu, Stephen S Rich, Simon R Cox, Judith M Vonk, Ivana Prokić, 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, Ma'en Obeidat, Myriam Fornage, Tianyuan Wang, James M Ward, Gerard H Koppelman, H Marike Boezen, Stephanie J London^*

^*Corresponding author voor dit werk

Onderzoeksoutput › Academic › peer review

19 Citaten (Scopus)

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RATIONALE: Methylation integrates factors present at birth and modifiable across life 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 Illumina450K or EPIC/850K arrays, with FEV1, FVC, and FEV1/FVC. We performed multi-ancestry epigenome-wide meta-analyses (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 (FDR<0.025) in relation to FEV1, FVC, or FEV1/FVC, including 1,240 novel and 73 also related to COPD (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 EWAS 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.

Originele taal-2	English
Pagina's (van-tot)	321-336
Aantal pagina's	16
Tijdschrift	American Journal of Respiratory and Critical Care Medicine
Volume	206
Nummer van het tijdschrift	3
Vroegere onlinedatum	2022
DOI's	https://doi.org/10.1164/rccm.202108-1907OC
Status	Published - 1-aug.-2022

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10.1164/rccm.202108-1907OCLicentie: CC BY-NC-ND

Pulmonary Function and Blood DNA Methylation A Multiancestry Epigenome-Wide Association Meta-analysisFinal publisher's version, 1,31 MBLicentie: CC BY-NC-ND

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BIOS consortium, GoDMC, Lee, M., Huan, T., McCartney, D. L., Chittoor, G., de Vries, M., Lahousse, L., Nguyen, J. N., Brody, J. A., Castillo-Fernandez, J., Terzikhan, N., Qi, C., Joehanes, R., Min, J. L., Smilnak, G. J., Shaw, J. R., Yang, C. X., Colicino, E., Hoang, T. T., ... London, S. J. (2022). Pulmonary Function and Blood DNA Methylation: A Multi-Ancestry Epigenome-Wide Association Meta-Analysis. American Journal of Respiratory and Critical Care Medicine, 206(3), 321-336. https://doi.org/10.1164/rccm.202108-1907OC

@article{23706f8ebdbe46f8ae50744bd1c9761d,

title = "Pulmonary Function and Blood DNA Methylation: A Multi-Ancestry Epigenome-Wide Association Meta-Analysis",

abstract = "RATIONALE: Methylation integrates factors present at birth and modifiable across life 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 Illumina450K or EPIC/850K arrays, with FEV1, FVC, and FEV1/FVC. We performed multi-ancestry epigenome-wide meta-analyses (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 (FDR<0.025) in relation to FEV1, FVC, or FEV1/FVC, including 1,240 novel and 73 also related to COPD (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 EWAS 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.",

author = "{BIOS consortium, GoDMC} and Mikyeong Lee and Tianxiao Huan and McCartney, {Daniel L} and Geetha Chittoor and {de Vries}, Maaike and Lies Lahousse and Nguyen, {Jennifer N} and Brody, {Jennifer A} and Juan Castillo-Fernandez and Natalie Terzikhan and Cancan Qi and Roby Joehanes and Min, {Josine L} and Smilnak, {Gordon J} and Shaw, {Jessica R} and Yang, {Chen Xi} and Elena Colicino and Hoang, {Thanh T} and Bermingham, {Mairead L} and Hanfei Xu and Justice, {Anne E} and Cheng-Jian Xu and Rich, {Stephen S} and Cox, {Simon R} and Vonk, {Judith M} and Ivana Proki{\'c} and Nona Sotoodehnia and Pei-Chien Tsai and Schwartz, {Joel D} and Leung, {Janice M} and Sinjini Sikdar and Walker, {Rosie M} and Harris, {Sarah E} and {van der Plaat}, {Diana A} and {Van Den Berg}, {David J} and Bartz, {Traci M} and Spector, {Tim D} and Vokonas, {Pantel S} and Marioni, {Riccardo E} and Taylor, {Adele M} and Yongmei Liu and Barr, {R Graham} and Lange, {Leslie A} and Baccarelli, {Andrea A} and Ma'en Obeidat and Myriam Fornage and Tianyuan Wang and Ward, {James M} and Koppelman, {Gerard H} and Boezen, {H Marike} and London, {Stephanie J}",

year = "2022",

month = aug,

day = "1",

doi = "10.1164/rccm.202108-1907OC",

language = "English",

volume = "206",

pages = "321--336",

journal = "American Journal of Respiratory and Critical Care Medicine",

issn = "1073-449X",

publisher = "AMER THORACIC SOC",

number = "3",

}

BIOS consortium, GoDMC, 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, C-J, Rich, SS, Cox, SR, Vonk, JM, Prokić, I, Sotoodehnia, N, Tsai, P-C, 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, Koppelman, GH, Boezen, HM & London, SJ 2022, 'Pulmonary Function and Blood DNA Methylation: A Multi-Ancestry Epigenome-Wide Association Meta-Analysis', American Journal of Respiratory and Critical Care Medicine, vol. 206, nr. 3, blz. 321-336. https://doi.org/10.1164/rccm.202108-1907OC

TY - JOUR

T1 - Pulmonary Function and Blood DNA Methylation

T2 - A Multi-Ancestry Epigenome-Wide Association Meta-Analysis

AU - BIOS consortium, GoDMC

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 - Prokić, 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, Ma'en

AU - Fornage, Myriam

AU - Wang, Tianyuan

AU - Ward, James M

AU - Koppelman, Gerard H

AU - Boezen, H Marike

AU - London, Stephanie J

PY - 2022/8/1

Y1 - 2022/8/1

N2 - RATIONALE: Methylation integrates factors present at birth and modifiable across life 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 Illumina450K or EPIC/850K arrays, with FEV1, FVC, and FEV1/FVC. We performed multi-ancestry epigenome-wide meta-analyses (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 (FDR<0.025) in relation to FEV1, FVC, or FEV1/FVC, including 1,240 novel and 73 also related to COPD (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 EWAS 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 life 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 Illumina450K or EPIC/850K arrays, with FEV1, FVC, and FEV1/FVC. We performed multi-ancestry epigenome-wide meta-analyses (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 (FDR<0.025) in relation to FEV1, FVC, or FEV1/FVC, including 1,240 novel and 73 also related to COPD (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 EWAS 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.

U2 - 10.1164/rccm.202108-1907OC

DO - 10.1164/rccm.202108-1907OC

M3 - Article

C2 - 35536696

SN - 1073-449X

VL - 206

SP - 321

EP - 336

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

IS - 3

ER -

Pulmonary Function and Blood DNA Methylation: A Multi-Ancestry Epigenome-Wide Association Meta-Analysis

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