DNA methylation at birth is associated with lung function development until age 26 years

Nandini Mukherjee; Ryan Arathimos; Su Chen; Parnian Kheirkhah Rahimabad; Luhang Han; Hongmei Zhang; John W Holloway; Caroline Relton; A John Henderson; Syed Hasan Arshad; Susan Ewart; Wilfried Karmaus

doi:10.1183/13993003.03505-2020

DNA methylation at birth is associated with lung function development until age 26 years

Nandini Mukherjee, Ryan Arathimos, Su Chen, Parnian Kheirkhah Rahimabad, Luhang Han, Hongmei Zhang, John W Holloway, Caroline Relton, A John Henderson, Syed Hasan Arshad, Susan Ewart, Wilfried Karmaus^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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Abstract

Little is known about whether DNA methylation (DNAm) of cytosine-phosphate-guanine (CpG) sites at birth predicts patterns of lung function development. We used heel prick DNAm from the F1-generation of Isle of Wight birth cohort (IOWBC-F1) for discovery of CpGs associated with lung function trajectories (Forced Expiratory Volume, Forced Vital Capacity, their ratio, and Forced Expiratory Flow at 25-75%) over the first 26 years, stratified by sex. We replicated the findings in the Avon Longitudinal Study of Parents and Children (ALSPAC) using cord blood DNAm.

Epigenome-wide screening was applied to identify CpGs associated with lung function trajectories in 396 boys, and 390 girls of IOWBC-F1. Replication in ALSPAC focused on lung function at ages 8, 15 and 24 years. Statistically significantly replicated CpGs were investigated for consistency in direction of association between cohorts, stability of DNAm over time in IOWBC-F1, relevant biological processes, and for association with gene expression (n=161) in IOWBC F2-generation (IOWBC-F2).

Differential DNAm of 8 CpGs on genes GLUL, MYCN, HLX, LHX1, COBL, COL18A1,
STRA6, and WNT11 involved in developmental processes, were significantly associated with lung function in the same direction in IOWBC-F1 and ALSPAC, and showed stable patterns at birth, age 10 and 18 years between high and low lung function trajectories in IOWBC-F1. CpGs on LHX1 and COL18A1 were linked to gene expression in IOWBCF2.

In two large cohorts, novel DNAm at birth were associated with patterns of lung function in adolescence and early adulthood providing possible targets for preventative interventions against adverse pulmonary function development.

Original language	English
Article number	2003505
Journal	European Respiratory Journal
Volume	57
Issue number	4
DOIs	https://doi.org/10.1183/13993003.03505-2020
Publication status	Published - 15 Apr 2021

Bibliographical note

Funding Information:
The authors gratefully acknowledge the participation and cooperation of the children and parents of Isle of Wight and appreciate the hard work of Sharon Matthews and the Isle of Wight research team in collecting data and Nikki Graham for technical support. 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) for the generation of the methylation data. 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. We would like to thank Gemma Sharp for her contribution towards the quality control of the ARIES data. This work has been supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases (R01 AI091905 and R01HL132321 to W.K., R01 AI121226 to H.Z. and J.W.H.); National Asthma Campaign, UK (364); and the National Institutes of Health/National Heart, Lung, and Blood Institute (R01 HL082925 to S.H.A.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, USA, and National Asthma Campaign, UK. The Accessible Resource for Integrated Epigenomics Studies (ARIES) which generated large scale methylation data was funded by the UK Biotechnology and Biological Sciences Research Council (BB/I025751/1 and BB/I025263/1). Additional epigenetic profiling on the ALSPAC cohort was supported by the UK Medical Research Council Integrative Epidemiology Unit and the University of Bristol (MC_UU_12013_1, MC_UU_12013_2, MC_UU_12013_5 and MC_UU_12013_8), the Wellcome Trust (WT088806) and the United States National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK10324). The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Funding information for this article has been deposited with the Crossref Funder Registry.

Funding Information:
Support statement: This work has been supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases (R01 AI091905 and R01HL132321 to W.K., R01 AI121226 to H.Z. and J.W.H.); National Asthma Campaign, UK (364); and the National Institutes of Health/National Heart, Lung, and Blood Institute (R01 HL082925 to S.H.A.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, USA, and National Asthma Campaign, UK. The Accessible Resource for Integrated Epigenomics Studies (ARIES) which generated large scale methylation data was funded by the UK Biotechnology and Biological Sciences Research Council (BB/I025751/1 and BB/I025263/1). Additional epigenetic profiling on the ALSPAC cohort was supported by the UK Medical Research Council Integrative Epidemiology Unit and the University of Bristol (MC_UU_12013_1, MC_UU_12013_2, MC_UU_12013_5 and MC_UU_12013_8), the Wellcome Trust (WT088806) and the United States National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK10324). The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Funding information for this article has been deposited with the Crossref Funder Registry.

Funding Information:
Acknowledgements: The authors gratefully acknowledge the participation and cooperation of the children and parents of Isle of Wight and appreciate the hard work of Sharon Matthews and the Isle of Wight research team in collecting data and Nikki Graham for technical support. 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) for the generation of the methylation data. 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. We would like to thank Gemma Sharp for her contribution towards the quality control of the ARIES data.

Publisher Copyright:
© ERS 2021

Keywords

DNA-methylation pattern
epigenome-wide
lung function trajectories
prospective
cohort study

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@article{5099eac95452436384e238ab42f03ce3,

title = "DNA methylation at birth is associated with lung function development until age 26 years",

abstract = "Little is known about whether DNA methylation (DNAm) of cytosine-phosphate-guanine (CpG) sites at birth predicts patterns of lung function development. We used heel prick DNAm from the F1-generation of Isle of Wight birth cohort (IOWBC-F1) for discovery of CpGs associated with lung function trajectories (Forced Expiratory Volume, Forced Vital Capacity, their ratio, and Forced Expiratory Flow at 25-75%) over the first 26 years, stratified by sex. We replicated the findings in the Avon Longitudinal Study of Parents and Children (ALSPAC) using cord blood DNAm.Epigenome-wide screening was applied to identify CpGs associated with lung function trajectories in 396 boys, and 390 girls of IOWBC-F1. Replication in ALSPAC focused on lung function at ages 8, 15 and 24 years. Statistically significantly replicated CpGs were investigated for consistency in direction of association between cohorts, stability of DNAm over time in IOWBC-F1, relevant biological processes, and for association with gene expression (n=161) in IOWBC F2-generation (IOWBC-F2).Differential DNAm of 8 CpGs on genes GLUL, MYCN, HLX, LHX1, COBL, COL18A1,STRA6, and WNT11 involved in developmental processes, were significantly associated with lung function in the same direction in IOWBC-F1 and ALSPAC, and showed stable patterns at birth, age 10 and 18 years between high and low lung function trajectories in IOWBC-F1. CpGs on LHX1 and COL18A1 were linked to gene expression in IOWBCF2.In two large cohorts, novel DNAm at birth were associated with patterns of lung function in adolescence and early adulthood providing possible targets for preventative interventions against adverse pulmonary function development.",

keywords = "DNA-methylation pattern, epigenome-wide, lung function trajectories, prospective, cohort study",

author = "Nandini Mukherjee and Ryan Arathimos and Su Chen and {Kheirkhah Rahimabad}, Parnian and Luhang Han and Hongmei Zhang and Holloway, {John W} and Caroline Relton and Henderson, {A John} and Arshad, {Syed Hasan} and Susan Ewart and Wilfried Karmaus",

note = "Funding Information: The authors gratefully acknowledge the participation and cooperation of the children and parents of Isle of Wight and appreciate the hard work of Sharon Matthews and the Isle of Wight research team in collecting data and Nikki Graham for technical support. 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) for the generation of the methylation data. 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. We would like to thank Gemma Sharp for her contribution towards the quality control of the ARIES data. This work has been supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases (R01 AI091905 and R01HL132321 to W.K., R01 AI121226 to H.Z. and J.W.H.); National Asthma Campaign, UK (364); and the National Institutes of Health/National Heart, Lung, and Blood Institute (R01 HL082925 to S.H.A.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, USA, and National Asthma Campaign, UK. The Accessible Resource for Integrated Epigenomics Studies (ARIES) which generated large scale methylation data was funded by the UK Biotechnology and Biological Sciences Research Council (BB/I025751/1 and BB/I025263/1). Additional epigenetic profiling on the ALSPAC cohort was supported by the UK Medical Research Council Integrative Epidemiology Unit and the University of Bristol (MC_UU_12013_1, MC_UU_12013_2, MC_UU_12013_5 and MC_UU_12013_8), the Wellcome Trust (WT088806) and the United States National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK10324). The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Funding information for this article has been deposited with the Crossref Funder Registry. Funding Information: Support statement: This work has been supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases (R01 AI091905 and R01HL132321 to W.K., R01 AI121226 to H.Z. and J.W.H.); National Asthma Campaign, UK (364); and the National Institutes of Health/National Heart, Lung, and Blood Institute (R01 HL082925 to S.H.A.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, USA, and National Asthma Campaign, UK. The Accessible Resource for Integrated Epigenomics Studies (ARIES) which generated large scale methylation data was funded by the UK Biotechnology and Biological Sciences Research Council (BB/I025751/1 and BB/I025263/1). Additional epigenetic profiling on the ALSPAC cohort was supported by the UK Medical Research Council Integrative Epidemiology Unit and the University of Bristol (MC_UU_12013_1, MC_UU_12013_2, MC_UU_12013_5 and MC_UU_12013_8), the Wellcome Trust (WT088806) and the United States National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK10324). The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Funding information for this article has been deposited with the Crossref Funder Registry. Funding Information: Acknowledgements: The authors gratefully acknowledge the participation and cooperation of the children and parents of Isle of Wight and appreciate the hard work of Sharon Matthews and the Isle of Wight research team in collecting data and Nikki Graham for technical support. 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) for the generation of the methylation data. 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. We would like to thank Gemma Sharp for her contribution towards the quality control of the ARIES data. Publisher Copyright: {\textcopyright} ERS 2021",

year = "2021",

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day = "15",

doi = "10.1183/13993003.03505-2020",

language = "English",

volume = "57",

journal = "European Respiratory Journal",

issn = "0903-1936",

publisher = "European Respiratory Society",

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TY - JOUR

T1 - DNA methylation at birth is associated with lung function development until age 26 years

AU - Mukherjee, Nandini

AU - Arathimos, Ryan

AU - Chen, Su

AU - Kheirkhah Rahimabad, Parnian

AU - Han, Luhang

AU - Zhang, Hongmei

AU - Holloway, John W

AU - Relton, Caroline

AU - Henderson, A John

AU - Arshad, Syed Hasan

AU - Ewart, Susan

AU - Karmaus, Wilfried

N1 - Funding Information: The authors gratefully acknowledge the participation and cooperation of the children and parents of Isle of Wight and appreciate the hard work of Sharon Matthews and the Isle of Wight research team in collecting data and Nikki Graham for technical support. 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) for the generation of the methylation data. 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. We would like to thank Gemma Sharp for her contribution towards the quality control of the ARIES data. This work has been supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases (R01 AI091905 and R01HL132321 to W.K., R01 AI121226 to H.Z. and J.W.H.); National Asthma Campaign, UK (364); and the National Institutes of Health/National Heart, Lung, and Blood Institute (R01 HL082925 to S.H.A.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, USA, and National Asthma Campaign, UK. The Accessible Resource for Integrated Epigenomics Studies (ARIES) which generated large scale methylation data was funded by the UK Biotechnology and Biological Sciences Research Council (BB/I025751/1 and BB/I025263/1). Additional epigenetic profiling on the ALSPAC cohort was supported by the UK Medical Research Council Integrative Epidemiology Unit and the University of Bristol (MC_UU_12013_1, MC_UU_12013_2, MC_UU_12013_5 and MC_UU_12013_8), the Wellcome Trust (WT088806) and the United States National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK10324). The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Funding information for this article has been deposited with the Crossref Funder Registry. Funding Information: Support statement: This work has been supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases (R01 AI091905 and R01HL132321 to W.K., R01 AI121226 to H.Z. and J.W.H.); National Asthma Campaign, UK (364); and the National Institutes of Health/National Heart, Lung, and Blood Institute (R01 HL082925 to S.H.A.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, USA, and National Asthma Campaign, UK. The Accessible Resource for Integrated Epigenomics Studies (ARIES) which generated large scale methylation data was funded by the UK Biotechnology and Biological Sciences Research Council (BB/I025751/1 and BB/I025263/1). Additional epigenetic profiling on the ALSPAC cohort was supported by the UK Medical Research Council Integrative Epidemiology Unit and the University of Bristol (MC_UU_12013_1, MC_UU_12013_2, MC_UU_12013_5 and MC_UU_12013_8), the Wellcome Trust (WT088806) and the United States National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK10324). The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Funding information for this article has been deposited with the Crossref Funder Registry. Funding Information: Acknowledgements: The authors gratefully acknowledge the participation and cooperation of the children and parents of Isle of Wight and appreciate the hard work of Sharon Matthews and the Isle of Wight research team in collecting data and Nikki Graham for technical support. 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) for the generation of the methylation data. 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. We would like to thank Gemma Sharp for her contribution towards the quality control of the ARIES data. Publisher Copyright: © ERS 2021

PY - 2021/4/15

Y1 - 2021/4/15

N2 - Little is known about whether DNA methylation (DNAm) of cytosine-phosphate-guanine (CpG) sites at birth predicts patterns of lung function development. We used heel prick DNAm from the F1-generation of Isle of Wight birth cohort (IOWBC-F1) for discovery of CpGs associated with lung function trajectories (Forced Expiratory Volume, Forced Vital Capacity, their ratio, and Forced Expiratory Flow at 25-75%) over the first 26 years, stratified by sex. We replicated the findings in the Avon Longitudinal Study of Parents and Children (ALSPAC) using cord blood DNAm.Epigenome-wide screening was applied to identify CpGs associated with lung function trajectories in 396 boys, and 390 girls of IOWBC-F1. Replication in ALSPAC focused on lung function at ages 8, 15 and 24 years. Statistically significantly replicated CpGs were investigated for consistency in direction of association between cohorts, stability of DNAm over time in IOWBC-F1, relevant biological processes, and for association with gene expression (n=161) in IOWBC F2-generation (IOWBC-F2).Differential DNAm of 8 CpGs on genes GLUL, MYCN, HLX, LHX1, COBL, COL18A1,STRA6, and WNT11 involved in developmental processes, were significantly associated with lung function in the same direction in IOWBC-F1 and ALSPAC, and showed stable patterns at birth, age 10 and 18 years between high and low lung function trajectories in IOWBC-F1. CpGs on LHX1 and COL18A1 were linked to gene expression in IOWBCF2.In two large cohorts, novel DNAm at birth were associated with patterns of lung function in adolescence and early adulthood providing possible targets for preventative interventions against adverse pulmonary function development.

AB - Little is known about whether DNA methylation (DNAm) of cytosine-phosphate-guanine (CpG) sites at birth predicts patterns of lung function development. We used heel prick DNAm from the F1-generation of Isle of Wight birth cohort (IOWBC-F1) for discovery of CpGs associated with lung function trajectories (Forced Expiratory Volume, Forced Vital Capacity, their ratio, and Forced Expiratory Flow at 25-75%) over the first 26 years, stratified by sex. We replicated the findings in the Avon Longitudinal Study of Parents and Children (ALSPAC) using cord blood DNAm.Epigenome-wide screening was applied to identify CpGs associated with lung function trajectories in 396 boys, and 390 girls of IOWBC-F1. Replication in ALSPAC focused on lung function at ages 8, 15 and 24 years. Statistically significantly replicated CpGs were investigated for consistency in direction of association between cohorts, stability of DNAm over time in IOWBC-F1, relevant biological processes, and for association with gene expression (n=161) in IOWBC F2-generation (IOWBC-F2).Differential DNAm of 8 CpGs on genes GLUL, MYCN, HLX, LHX1, COBL, COL18A1,STRA6, and WNT11 involved in developmental processes, were significantly associated with lung function in the same direction in IOWBC-F1 and ALSPAC, and showed stable patterns at birth, age 10 and 18 years between high and low lung function trajectories in IOWBC-F1. CpGs on LHX1 and COL18A1 were linked to gene expression in IOWBCF2.In two large cohorts, novel DNAm at birth were associated with patterns of lung function in adolescence and early adulthood providing possible targets for preventative interventions against adverse pulmonary function development.

KW - DNA-methylation pattern

KW - epigenome-wide

KW - lung function trajectories

KW - prospective

KW - cohort study

U2 - 10.1183/13993003.03505-2020

DO - 10.1183/13993003.03505-2020

M3 - Article (Academic Journal)

C2 - 33214203

SN - 0903-1936

VL - 57

JO - European Respiratory Journal

JF - European Respiratory Journal

IS - 4

M1 - 2003505

ER -

DNA methylation at birth is associated with lung function development until age 26 years

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