Epigenome-wide meta-analysis of DNA methylation and childhood asthma

Sarah E. Reese; Cheng-Jian Xu; Herman T. Den Dekker; Mi Kyeong Lee; Sinjini Sikdar; Carlos Ruiz-Arenas; Simon K. Merid; Faisal I Rezwan; Christian M. Page; Vilhelmina Ullemar; Phillip E. Melton; Sam S. Oh; Ivana V. Yang; Kimberley Burrows; Cilla Söderhäll; Dereje D. Jima; Lu Gao; Ryan Arathimos; Leanne K. Küpers; Matthias Wielscher; Peter Rzehak; Jari Lahti; Catherine Laprise; Anne-Marie Madore; James Ward; Brian D. Bennett; Tianyuan Wang; Douglas A. Bell; Judith M. Vonk; Siri E. Håberg; Shanshan Zhao; Robert Karlsson; Elysia Hollams; Donglei Hu; Adam J. Richards; Anna Bergström; Gemma C. Sharp; Janine F. Felix; Mariona Bustamante; Olena Gruzieva; Rachel L. Maguire; Frank Gilliland; Nour Baïz; Ellen A. Nohr; Eva Corpeleijn; Sylvain Sebert; Wilfried Karmaus; Veit Grote; Eero Kajantie; Maria C. Magnus; Anne K. Örtqvist; Celeste Eng; Andrew H. Liu; Inger Kull; Vincent W. V. Jaddoe; Jordi Sunyer; Juha Kere; Cathrine Hoyo; Isabella Annesi-Maesano; Syed Hasan Arshad; Berthold Koletzko; Bert Brunekreef; Elisabeth B. Binder; Katri Räikkönen; Eva Reischl; John W. Holloway; Marjo-Riitta Jarvelin; Harold Snieder; Nabila Kazmi; Carrie V. Breton; Susan K. Murphy; Göran Pershagen; Josep Maria Anto; Caroline L. Relton; David A. Schwartz; Esteban G. Burchard; Rae-Chi Huang; Wenche Nystad; Catarina Almqvist; A. John Henderson; Erik Melén; Liesbeth Duijts; Gerard H. Koppelman; Stephanie J. London; The Bios Consortium

doi:10.1016/j.jaci.2018.11.043

Epigenome-wide meta-analysis of DNA methylation and childhood asthma

Sarah E. Reese, Cheng-Jian Xu, Herman T. Den Dekker, Mi Kyeong Lee, Sinjini Sikdar, Carlos Ruiz-Arenas, Simon K. Merid, Faisal I Rezwan, Christian M. Page, Vilhelmina Ullemar, Phillip E. Melton, Sam S. Oh, Ivana V. Yang, Kimberley Burrows, Cilla Söderhäll, Dereje D. Jima, Lu Gao, Ryan Arathimos, Leanne K. Küpers, Matthias WielscherPeter Rzehak, Jari Lahti, Catherine Laprise, Anne-Marie Madore, James Ward, Brian D. Bennett, Tianyuan Wang, Douglas A. Bell, Judith M. Vonk, Siri E. Håberg, Shanshan Zhao, Robert Karlsson, Elysia Hollams, Donglei Hu, Adam J. Richards, Anna Bergström, Gemma C. Sharp, Janine F. Felix, Mariona Bustamante, Olena Gruzieva, Rachel L. Maguire, Frank Gilliland, Nour Baïz, Ellen A. Nohr, Eva Corpeleijn, Sylvain Sebert, Wilfried Karmaus, Veit Grote, Eero Kajantie, Maria C. Magnus, Anne K. Örtqvist, Celeste Eng, Andrew H. Liu, Inger Kull, Vincent W. V. Jaddoe, Jordi Sunyer, Juha Kere, Cathrine Hoyo, Isabella Annesi-Maesano, Syed Hasan Arshad, Berthold Koletzko, Bert Brunekreef, Elisabeth B. Binder, Katri Räikkönen, Eva Reischl, John W. Holloway, Marjo-Riitta Jarvelin, Harold Snieder, Nabila Kazmi, Carrie V. Breton, Susan K. Murphy, Göran Pershagen, Josep Maria Anto, Caroline L. Relton, David A. Schwartz, Esteban G. Burchard, Rae-Chi Huang, Wenche Nystad, Catarina Almqvist, A. John Henderson, Erik Melén, Liesbeth Duijts, Gerard H. Koppelman, Stephanie J. London, The Bios Consortium

Department of Computer Science

Research output: Contribution to journal › Article › peer-review

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Abstract

BACKGROUND: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis.

OBJECTIVE: We sought to identify differential DNA methylation in newborns and children related to childhood asthma.

METHODS: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions.

RESULTS: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2.

CONCLUSION: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.

Original language	English
Pages (from-to)	2062-2074
Number of pages	13
Journal	Journal of Allergy and Clinical Immunology
Volume	143
Issue number	6
Early online date	21 Nov 2018
DOIs	https://doi.org/10.1016/j.jaci.2018.11.043
Publication status	Published - 05 Jun 2019

Keywords

Epigenetics
asthma
childhood
drug development
methylation
newborn
Asthma/genetics
Genome-Wide Association Study
Cross-Sectional Studies
Epigenesis, Genetic
Humans
Interleukin-5 Receptor alpha Subunit/genetics
CpG Islands/genetics
DNA Methylation
Epigenome/genetics
ERG1 Potassium Channel/genetics
Child
Infant, Newborn

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Reese, S. E., Xu, C.-J., Dekker, H. T. D., Lee, M. K., Sikdar, S., Ruiz-Arenas, C., Merid, S. K., Rezwan, F. I., Page, C. M., Ullemar, V., Melton, P. E., Oh, S. S., Yang, I. V., Burrows, K., Söderhäll, C., Jima, D. D., Gao, L., Arathimos, R., Küpers, L. K., ... Consortium, T. B. (2019). Epigenome-wide meta-analysis of DNA methylation and childhood asthma. Journal of Allergy and Clinical Immunology, 143(6), 2062-2074. https://doi.org/10.1016/j.jaci.2018.11.043

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abstract = "BACKGROUND: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis.OBJECTIVE: We sought to identify differential DNA methylation in newborns and children related to childhood asthma.METHODS: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions.RESULTS: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2.CONCLUSION: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.",

keywords = "Epigenetics, asthma, childhood, drug development, methylation, newborn, Asthma/genetics, Genome-Wide Association Study, Cross-Sectional Studies, Epigenesis, Genetic, Humans, Interleukin-5 Receptor alpha Subunit/genetics, CpG Islands/genetics, DNA Methylation, Epigenome/genetics, ERG1 Potassium Channel/genetics, Child, Infant, Newborn",

author = "Reese, {Sarah E.} and Cheng-Jian Xu and Dekker, {Herman T. Den} and Lee, {Mi Kyeong} and Sinjini Sikdar and Carlos Ruiz-Arenas and Merid, {Simon K.} and Rezwan, {Faisal I} and Page, {Christian M.} and Vilhelmina Ullemar and Melton, {Phillip E.} and Oh, {Sam S.} and Yang, {Ivana V.} and Kimberley Burrows and Cilla S{\"o}derh{\"a}ll and Jima, {Dereje D.} and Lu Gao and Ryan Arathimos and K{\"u}pers, {Leanne K.} and Matthias Wielscher and Peter Rzehak and Jari Lahti and Catherine Laprise and Anne-Marie Madore and James Ward and Bennett, {Brian D.} and Tianyuan Wang and Bell, {Douglas A.} and Vonk, {Judith M.} and H{\aa}berg, {Siri E.} and Shanshan Zhao and Robert Karlsson and Elysia Hollams and Donglei Hu and Richards, {Adam J.} and Anna Bergstr{\"o}m and Sharp, {Gemma C.} and Felix, {Janine F.} and Mariona Bustamante and Olena Gruzieva and Maguire, {Rachel L.} and Frank Gilliland and Nour Ba{\"i}z and Nohr, {Ellen A.} and Eva Corpeleijn and Sylvain Sebert and Wilfried Karmaus and Veit Grote and Eero Kajantie and Magnus, {Maria C.} and {\"O}rtqvist, {Anne K.} and Celeste Eng and Liu, {Andrew H.} and Inger Kull and Jaddoe, {Vincent W. V.} and Jordi Sunyer and Juha Kere and Cathrine Hoyo and Isabella Annesi-Maesano and Arshad, {Syed Hasan} and Berthold Koletzko and Bert Brunekreef and Binder, {Elisabeth B.} and Katri R{\"a}ikk{\"o}nen and Eva Reischl and Holloway, {John W.} and Marjo-Riitta Jarvelin and Harold Snieder and Nabila Kazmi and Breton, {Carrie V.} and Murphy, {Susan K.} and G{\"o}ran Pershagen and Anto, {Josep Maria} and Relton, {Caroline L.} and Schwartz, {David A.} and Burchard, {Esteban G.} and Rae-Chi Huang and Wenche Nystad and Catarina Almqvist and Henderson, {A. John} and Erik Mel{\'e}n and Liesbeth Duijts and Koppelman, {Gerard H.} and London, {Stephanie J.} and Consortium, {The Bios}",

note = "Published by Elsevier Inc.",

year = "2019",

month = jun,

day = "5",

doi = "10.1016/j.jaci.2018.11.043",

language = "English",

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pages = "2062--2074",

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Reese, SE, Xu, C-J, Dekker, HTD, Lee, MK, Sikdar, S, Ruiz-Arenas, C, Merid, SK, Rezwan, FI, Page, CM, Ullemar, V, Melton, PE, Oh, SS, Yang, IV, Burrows, K, Söderhäll, C, Jima, DD, Gao, L, Arathimos, R, Küpers, LK, Wielscher, M, Rzehak, P, Lahti, J, Laprise, C, Madore, A-M, Ward, J, Bennett, BD, Wang, T, Bell, DA, Vonk, JM, Håberg, SE, Zhao, S, Karlsson, R, Hollams, E, Hu, D, Richards, AJ, Bergström, A, Sharp, GC, Felix, JF, Bustamante, M, Gruzieva, O, Maguire, RL, Gilliland, F, Baïz, N, Nohr, EA, Corpeleijn, E, Sebert, S, Karmaus, W, Grote, V, Kajantie, E, Magnus, MC, Örtqvist, AK, Eng, C, Liu, AH, Kull, I, Jaddoe, VWV, Sunyer, J, Kere, J, Hoyo, C, Annesi-Maesano, I, Arshad, SH, Koletzko, B, Brunekreef, B, Binder, EB, Räikkönen, K, Reischl, E, Holloway, JW, Jarvelin, M-R, Snieder, H, Kazmi, N, Breton, CV, Murphy, SK, Pershagen, G, Anto, JM, Relton, CL, Schwartz, DA, Burchard, EG, Huang, R-C, Nystad, W, Almqvist, C, Henderson, AJ, Melén, E, Duijts, L, Koppelman, GH, London, SJ & Consortium, TB 2019, 'Epigenome-wide meta-analysis of DNA methylation and childhood asthma', Journal of Allergy and Clinical Immunology, vol. 143, no. 6, pp. 2062-2074. https://doi.org/10.1016/j.jaci.2018.11.043

TY - JOUR

T1 - Epigenome-wide meta-analysis of DNA methylation and childhood asthma

AU - Reese, Sarah E.

AU - Xu, Cheng-Jian

AU - Dekker, Herman T. Den

AU - Lee, Mi Kyeong

AU - Sikdar, Sinjini

AU - Ruiz-Arenas, Carlos

AU - Merid, Simon K.

AU - Rezwan, Faisal I

AU - Page, Christian M.

AU - Ullemar, Vilhelmina

AU - Melton, Phillip E.

AU - Oh, Sam S.

AU - Yang, Ivana V.

AU - Burrows, Kimberley

AU - Söderhäll, Cilla

AU - Jima, Dereje D.

AU - Gao, Lu

AU - Arathimos, Ryan

AU - Küpers, Leanne K.

AU - Wielscher, Matthias

AU - Rzehak, Peter

AU - Lahti, Jari

AU - Laprise, Catherine

AU - Madore, Anne-Marie

AU - Ward, James

AU - Bennett, Brian D.

AU - Wang, Tianyuan

AU - Bell, Douglas A.

AU - Vonk, Judith M.

AU - Håberg, Siri E.

AU - Zhao, Shanshan

AU - Karlsson, Robert

AU - Hollams, Elysia

AU - Hu, Donglei

AU - Richards, Adam J.

AU - Bergström, Anna

AU - Sharp, Gemma C.

AU - Felix, Janine F.

AU - Bustamante, Mariona

AU - Gruzieva, Olena

AU - Maguire, Rachel L.

AU - Gilliland, Frank

AU - Baïz, Nour

AU - Nohr, Ellen A.

AU - Corpeleijn, Eva

AU - Sebert, Sylvain

AU - Karmaus, Wilfried

AU - Grote, Veit

AU - Kajantie, Eero

AU - Magnus, Maria C.

AU - Örtqvist, Anne K.

AU - Eng, Celeste

AU - Liu, Andrew H.

AU - Kull, Inger

AU - Jaddoe, Vincent W. V.

AU - Sunyer, Jordi

AU - Kere, Juha

AU - Hoyo, Cathrine

AU - Annesi-Maesano, Isabella

AU - Arshad, Syed Hasan

AU - Koletzko, Berthold

AU - Brunekreef, Bert

AU - Binder, Elisabeth B.

AU - Räikkönen, Katri

AU - Reischl, Eva

AU - Holloway, John W.

AU - Jarvelin, Marjo-Riitta

AU - Snieder, Harold

AU - Kazmi, Nabila

AU - Breton, Carrie V.

AU - Murphy, Susan K.

AU - Pershagen, Göran

AU - Anto, Josep Maria

AU - Relton, Caroline L.

AU - Schwartz, David A.

AU - Burchard, Esteban G.

AU - Huang, Rae-Chi

AU - Nystad, Wenche

AU - Almqvist, Catarina

AU - Henderson, A. John

AU - Melén, Erik

AU - Duijts, Liesbeth

AU - Koppelman, Gerard H.

AU - London, Stephanie J.

AU - Consortium, The Bios

N1 - Published by Elsevier Inc.

PY - 2019/6/5

Y1 - 2019/6/5

N2 - BACKGROUND: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis.OBJECTIVE: We sought to identify differential DNA methylation in newborns and children related to childhood asthma.METHODS: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions.RESULTS: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2.CONCLUSION: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.

AB - BACKGROUND: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis.OBJECTIVE: We sought to identify differential DNA methylation in newborns and children related to childhood asthma.METHODS: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions.RESULTS: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2.CONCLUSION: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.

KW - Epigenetics

KW - asthma

KW - childhood

KW - drug development

KW - methylation

KW - newborn

KW - Asthma/genetics

KW - Genome-Wide Association Study

KW - Cross-Sectional Studies

KW - Epigenesis, Genetic

KW - Humans

KW - Interleukin-5 Receptor alpha Subunit/genetics

KW - CpG Islands/genetics

KW - DNA Methylation

KW - Epigenome/genetics

KW - ERG1 Potassium Channel/genetics

KW - Child

KW - Infant, Newborn

UR - http://www.scopus.com/inward/record.url?scp=85060282097&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2018.11.043

DO - 10.1016/j.jaci.2018.11.043

M3 - Article

C2 - 30579849

SN - 1097-6825

VL - 143

SP - 2062

EP - 2074

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 6

ER -

Epigenome-wide meta-analysis of DNA methylation and childhood asthma

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