Pre-adolescence DNA methylation is associated with lung function trajectories from pre-adolescence to adulthood
Pre-adolescence DNA methylation is associated with lung function trajectories from pre-adolescence to adulthood
BACKGROUND: The pattern of lung function development from pre-adolescence to adulthood plays a significant role in the pathogenesis of respiratory diseases. Inconsistent findings in genetic studies on lung function trajectories, the importance of DNA methylation (DNA-M), and the critical role of adolescence in lung function development motivated the present study of pre-adolescent DNA-M with lung function trajectories. This study investigated epigenome-wide associations of DNA-M at cytosine-phosphate-guanine dinucleotide sites (CpGs) at childhood with lung function trajectories from childhood to young adulthood.
METHODS: DNA-M was measured in peripheral blood at age 10 years in the Isle of Wight (IOW) birth cohort. Spirometry was conducted at ages 10, 18, and 26 years. A training/testing-based method was used to screen CpGs. Multivariable logistic regressions were applied to assess the association of DNA-M with lung function trajectories from pre-adolescence to adulthood. To detect differentially methylated regions (DMRs) among CpGs, DMR enrichment analysis was conducted. Findings were further tested in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Pathway analyses were performed on the mapped genes of the identified CpGs and DMRs. Biological relevance of the identified CpGs was assessed with gene expression. All analyses were stratified by sex.
RESULTS: High and low trajectories of FVC, FEV
1, and FEV
1/FVC in each sex were identified. At P
Bonferroni < 0.05, DNA-M at 96 distinct CpGs (41 in males) showed associations with FVC, FEV
1, and FEV
1/FVC trajectories in IOW cohort. These 95 CpGs (cg24000797 was disqualified) were further tested in ALSPAC; 44 CpGs (19 in males) of these 95 showed the same directions of association as in the IOW cohort; and three CpGs (two in males) were replicated. DNA-M at two and four CpGs showed significant associations with the corresponding gene expression in males and females, respectively. At P
FDR < 0.05, 23 and 10 DMRs were identified in males and females, respectively. Pathways were identified; some of those were linked to lung function and chronic obstructive lung diseases.
CONCLUSION: The identified CpGs at pre-adolescence have the potential to serve as candidate markers for lung function trajectory prediction and chronic lung diseases.
ALSPAC), Adolescence, COPD, DNA methylation, Epigenome-wide, Lung function trajectory, Population-based cohorts (IOW birth cohort
1-18
Sunny, Shadia Khan
a77127e5-1281-445d-b8cb-dd58fab1b63e
Zhang, Hongmei
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Mzayek, Fawaz
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Relton, Caroline L.
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Ring, Susan
79941daa-7ae8-47f1-beb4-e8560ce12fd8
Henderson, A. John
03d06941-3f2c-4a2e-998b-8d18124049d1
Ewart, Susan
28667421-3cf7-43d7-b1c3-ca27564938f7
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Arshad, Syed
917e246d-2e60-472f-8d30-94b01ef28958
6 January 2021
Sunny, Shadia Khan
a77127e5-1281-445d-b8cb-dd58fab1b63e
Zhang, Hongmei
9f774048-54d6-4321-a252-3887b2c76db0
Mzayek, Fawaz
0e635b70-c9f4-4cb0-a334-c75bb401559c
Relton, Caroline L.
7a9fe7f7-d14b-4bb7-be71-a3afa6ff8538
Ring, Susan
79941daa-7ae8-47f1-beb4-e8560ce12fd8
Henderson, A. John
03d06941-3f2c-4a2e-998b-8d18124049d1
Ewart, Susan
28667421-3cf7-43d7-b1c3-ca27564938f7
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Arshad, Syed
917e246d-2e60-472f-8d30-94b01ef28958
Sunny, Shadia Khan, Zhang, Hongmei, Mzayek, Fawaz, Relton, Caroline L., Ring, Susan, Henderson, A. John, Ewart, Susan, Holloway, John W. and Arshad, Syed
(2021)
Pre-adolescence DNA methylation is associated with lung function trajectories from pre-adolescence to adulthood.
Clinical Epigenetics, 13 (1), , [5].
(doi:10.1186/s13148-020-00992-5).
Abstract
BACKGROUND: The pattern of lung function development from pre-adolescence to adulthood plays a significant role in the pathogenesis of respiratory diseases. Inconsistent findings in genetic studies on lung function trajectories, the importance of DNA methylation (DNA-M), and the critical role of adolescence in lung function development motivated the present study of pre-adolescent DNA-M with lung function trajectories. This study investigated epigenome-wide associations of DNA-M at cytosine-phosphate-guanine dinucleotide sites (CpGs) at childhood with lung function trajectories from childhood to young adulthood.
METHODS: DNA-M was measured in peripheral blood at age 10 years in the Isle of Wight (IOW) birth cohort. Spirometry was conducted at ages 10, 18, and 26 years. A training/testing-based method was used to screen CpGs. Multivariable logistic regressions were applied to assess the association of DNA-M with lung function trajectories from pre-adolescence to adulthood. To detect differentially methylated regions (DMRs) among CpGs, DMR enrichment analysis was conducted. Findings were further tested in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Pathway analyses were performed on the mapped genes of the identified CpGs and DMRs. Biological relevance of the identified CpGs was assessed with gene expression. All analyses were stratified by sex.
RESULTS: High and low trajectories of FVC, FEV
1, and FEV
1/FVC in each sex were identified. At P
Bonferroni < 0.05, DNA-M at 96 distinct CpGs (41 in males) showed associations with FVC, FEV
1, and FEV
1/FVC trajectories in IOW cohort. These 95 CpGs (cg24000797 was disqualified) were further tested in ALSPAC; 44 CpGs (19 in males) of these 95 showed the same directions of association as in the IOW cohort; and three CpGs (two in males) were replicated. DNA-M at two and four CpGs showed significant associations with the corresponding gene expression in males and females, respectively. At P
FDR < 0.05, 23 and 10 DMRs were identified in males and females, respectively. Pathways were identified; some of those were linked to lung function and chronic obstructive lung diseases.
CONCLUSION: The identified CpGs at pre-adolescence have the potential to serve as candidate markers for lung function trajectory prediction and chronic lung diseases.
Text
s13148-020-00992-5
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Accepted/In Press date: 15 December 2020
Published date: 6 January 2021
Additional Information:
Funding Information:
The study conveyed in this publication was supported by the National Institute of Allergy and Infectious Diseases under Award Number R01 AI121226 (MPI: Hongmei Zhang and John Holloway). The 10-year follow-up of IOW cohort was funded by National Asthma Campaign, UK (Grant No 364), and the 18-year follow-up by a grant from the National Heart and Blood Institute (R01 HL082925, PI, SH Arshad). The UK Medical Research Council (MRC) and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). Generation of methylation array data was specifically funded by NIH R01AI121226, R01AI091905, BBSRC BBI025751/1, and BB/I025263/1, MRC MC_UU_12013/1, MC_UU_12013/2, MC_UU_12013/8. Lung function measurements were funded by grants from the MRC (G0401540/73080 and MR/M022501/1).
Funding Information:
The authors gratefully acknowledge the cooperation of the children and parents who participated in this study and appreciate the hard work of the Isle of Wight research team in collecting data. We thank the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust Grant Reference 090532/Z/09/Z and MRC Hub Grant G0900747 91070) for the generation of the methylation data. The authors are thankful to the High-Performance Computing facility at the University of Memphis. For the ALSPAC cohort, we are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses.
Publisher Copyright:
© 2021, The Author(s).
Keywords:
ALSPAC), Adolescence, COPD, DNA methylation, Epigenome-wide, Lung function trajectory, Population-based cohorts (IOW birth cohort
Identifiers
Local EPrints ID: 446507
URI: http://eprints.soton.ac.uk/id/eprint/446507
ISSN: 1868-7075
PURE UUID: 155b8001-1617-4ba2-9543-3cb07e18f4d8
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Date deposited: 11 Feb 2021 17:39
Last modified: 17 Mar 2024 02:45
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Contributors
Author:
Shadia Khan Sunny
Author:
Hongmei Zhang
Author:
Fawaz Mzayek
Author:
Caroline L. Relton
Author:
Susan Ring
Author:
A. John Henderson
Author:
Susan Ewart
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