Epigenome-wide Meta-analysis of DNA Methylation and Childhood Asthma

BIOS consortium

doi:10.1016/j.jaci.2018.11.043

Epigenome-wide Meta-analysis of DNA Methylation and Childhood Asthma

BIOS consortium

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

139 Citations (Scopus)

Abstract

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

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

METHODS: Within the Pregnancy And Childhood Epigenetics (PACE) 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-age children. We also identified differentially methylated regions (DMRs).

RESULTS: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, FDR<0.05) in relation to asthma development. In cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (FDR<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 regulatory impact 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 developing asthma by school age. Cross-sectional associations in children may reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children substantially replicated in eosinophils and respiratory epithelium.

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

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10.1016/j.jaci.2018.11.043Licence: CC BY

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@article{980cb22f6e26441ab41f189225c2df80,

title = "Epigenome-wide Meta-analysis of DNA Methylation and Childhood Asthma",

abstract = "BACKGROUND: Epigenetic mechanisms, including methylation, may contribute to childhood asthma. Identifying DNA methylation profiles in asthma may inform disease pathogenesis.OBJECTIVE: To identify differential DNA methylation in newborns and children related to childhood asthma.METHODS: Within the Pregnancy And Childhood Epigenetics (PACE) 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-age children. We also identified differentially methylated regions (DMRs).RESULTS: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, FDR<0.05) in relation to asthma development. In cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (FDR<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 regulatory impact 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 developing asthma by school age. Cross-sectional associations in children may reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children substantially replicated in eosinophils and respiratory epithelium.",

author = "{BIOS consortium} and Reese, {Sarah E} and Cheng-Jian Xu and {den Dekker}, {Herman T} 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}",

year = "2019",

month = jun,

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

language = "English",

volume = "143",

pages = "2062--2074",

journal = "The Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier - Mosby",

number = "6",

}

TY - JOUR

T1 - Epigenome-wide Meta-analysis of DNA Methylation and Childhood Asthma

AU - BIOS consortium

AU - Reese, Sarah E

AU - Xu, Cheng-Jian

AU - den Dekker, Herman T

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

PY - 2019/6

Y1 - 2019/6

N2 - BACKGROUND: Epigenetic mechanisms, including methylation, may contribute to childhood asthma. Identifying DNA methylation profiles in asthma may inform disease pathogenesis.OBJECTIVE: To identify differential DNA methylation in newborns and children related to childhood asthma.METHODS: Within the Pregnancy And Childhood Epigenetics (PACE) 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-age children. We also identified differentially methylated regions (DMRs).RESULTS: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, FDR<0.05) in relation to asthma development. In cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (FDR<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 regulatory impact 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 developing asthma by school age. Cross-sectional associations in children may reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children substantially replicated in eosinophils and respiratory epithelium.

AB - BACKGROUND: Epigenetic mechanisms, including methylation, may contribute to childhood asthma. Identifying DNA methylation profiles in asthma may inform disease pathogenesis.OBJECTIVE: To identify differential DNA methylation in newborns and children related to childhood asthma.METHODS: Within the Pregnancy And Childhood Epigenetics (PACE) 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-age children. We also identified differentially methylated regions (DMRs).RESULTS: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, FDR<0.05) in relation to asthma development. In cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (FDR<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 regulatory impact 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 developing asthma by school age. Cross-sectional associations in children may reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children substantially replicated in eosinophils and respiratory epithelium.

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DO - 10.1016/j.jaci.2018.11.043

M3 - Article

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VL - 143

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EP - 2074

JO - The Journal of Allergy and Clinical Immunology

JF - The Journal of Allergy and Clinical Immunology

IS - 6

ER -

Epigenome-wide Meta-analysis of DNA Methylation and Childhood Asthma

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