Meta-Analysis

. 2019 Jun;143(6):2062-2074.

doi: 10.1016/j.jaci.2018.11.043. Epub 2018 Dec 21.

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

Sarah E Reese¹, Cheng-Jian Xu², Herman T den Dekker³, Mi Kyeong Lee¹, Sinjini Sikdar¹, Carlos Ruiz-Arenas⁴, Simon K Merid⁵, Faisal I Rezwan⁶, Christian M Page⁷, Vilhelmina Ullemar⁸, Phillip E Melton⁹, Sam S Oh¹⁰, Ivana V Yang¹¹, Kimberley Burrows¹², Cilla Söderhäll¹³, Dereje D Jima¹⁴, Lu Gao¹⁵, Ryan Arathimos¹⁶, Leanne K Küpers¹⁷, Matthias Wielscher¹⁸, Peter Rzehak¹⁹, Jari Lahti²⁰, Catherine Laprise²¹, Anne-Marie Madore²², James Ward¹, Brian D Bennett¹, Tianyuan Wang¹, Douglas A Bell¹; BIOS consortium; Judith M Vonk²³, Siri E Håberg²⁴, Shanshan Zhao¹, Robert Karlsson⁸, Elysia Hollams²⁵, Donglei Hu¹⁰, Adam J Richards¹¹, Anna Bergström²⁶, Gemma C Sharp²⁷, Janine F Felix²⁸, Mariona Bustamante²⁹, Olena Gruzieva²⁶, Rachel L Maguire³⁰, Frank Gilliland¹⁵, Nour Baïz³¹, Ellen A Nohr³², Eva Corpeleijn³³, Sylvain Sebert³⁴, Wilfried Karmaus³⁵, Veit Grote¹⁹, Eero Kajantie³⁶, Maria C Magnus³⁷, Anne K Örtqvist⁸, Celeste Eng¹⁰, Andrew H Liu³⁸, Inger Kull³⁹, Vincent W V Jaddoe²⁸, Jordi Sunyer⁴⁰, Juha Kere⁴¹, Cathrine Hoyo⁴², Isabella Annesi-Maesano³¹, Syed Hasan Arshad⁴³, Berthold Koletzko¹⁹, Bert Brunekreef⁴⁴, Elisabeth B Binder⁴⁵, Katri Räikkönen⁴⁶, Eva Reischl⁴⁷, John W Holloway⁴⁸, Marjo-Riitta Jarvelin⁴⁹, Harold Snieder³³, Nabila Kazmi¹⁶, Carrie V Breton¹⁵, Susan K Murphy⁵⁰, Göran Pershagen²⁶, Josep Maria Anto⁴⁰, Caroline L Relton¹², David A Schwartz¹¹, Esteban G Burchard⁵¹, Rae-Chi Huang²⁵, Wenche Nystad²⁴, Catarina Almqvist⁵², A John Henderson⁵³, Erik Melén⁵⁴, Liesbeth Duijts⁵⁵, Gerard H Koppelman⁵⁶, Stephanie J London⁵⁷

Affiliations

¹ Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC.
² Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
³ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁴ CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; ISGlobal, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
⁵ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁶ Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
⁷ Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway; Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway.
⁸ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁹ Curtin/UWA Centre for Genetic Origins of Health and Disease, Faculty of Health and Medical Sciences, University of Western Australia, Crawley, Australia; School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Australia.
¹⁰ Department of Medicine, University of California San Francisco, San Francisco, Calif.
¹¹ Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colo.
¹² Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
¹³ Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
¹⁴ Bioinformatics Research Center, North Carolina State University, Raleigh, NC; Center for Human Health and the Environment, North Carolina State University, Raleigh, NC.
¹⁵ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
¹⁶ Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
¹⁷ Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹⁸ Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, United Kingdom.
¹⁹ Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, Ludwig-Maximilians Universität München (LMU), Munich, Germany.
²⁰ Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland; Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland.
²¹ Centre intégré universitaire de santé et de services sociaux du Saguenay, Saguenay, Quebec, Canada; Département des sciences fondamentales, Université du Québec à Chicoutimi, Saguenay, Quebec, Canada.
²² Département des sciences fondamentales, Université du Québec à Chicoutimi, Saguenay, Quebec, Canada.
²³ GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
²⁴ Division of Mental and Physical Health, Norwegian Institute of Public Health, Oslo, Norway.
²⁵ Telethon Kids Institute, University of Western Australia, Perth, Australia.
²⁶ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.
²⁷ Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; Bristol Dental School, University of Bristol, Bristol, United Kingdom.
²⁸ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
²⁹ CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; ISGlobal, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Barcelona, Spain.
³⁰ Department of Biological Sciences, North Carolina State University, Raleigh, NC; Department of Community and Family Medicine, Duke University Medical Center, Durham, NC.
³¹ Epidemiology of Allergic and Respiratory Diseases Department, IPLESP, INSERM and UPMC Sorbonne Université, Paris, France.
³² Research Unit for Gynaecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
³³ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
³⁴ Biocenter Oulu, University of Oulu, Oulu, Finland; Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland; Department of Genomics of Complex Diseases, School of Public Health, Imperial College London, London, United Kingdom.
³⁵ Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, Memphis, Tenn.
³⁶ Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland; Department of Obstetrics and Gynaecology, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland; Hospital for Children and Adolescents, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
³⁷ Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; Division of Mental and Physical Health, Norwegian Institute of Public Health, Oslo, Norway.
³⁸ Children's Hospital Colorado, Aurora, Colo.
³⁹ Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; Sachs' Children's Hospital, Södersjukhuset, Stockholm, Sweden.
⁴⁰ CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; ISGlobal, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
⁴¹ Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden; Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
⁴² Center for Human Health and the Environment, North Carolina State University, Raleigh, NC; Department of Biological Sciences, North Carolina State University, Raleigh, NC.
⁴³ Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; David Hide Asthma and Allergy Research Centre, Isle of Wight, United Kingdom.
⁴⁴ Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
⁴⁵ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Ga; Max-Planck-Institute of Psychiatry, Munich, Germany.
⁴⁶ Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland.
⁴⁷ Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum Muenchen, Munich, Germany.
⁴⁸ Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
⁴⁹ Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, United Kingdom; Biocenter Oulu, University of Oulu, Oulu, Finland; Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
⁵⁰ Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC; Nicholas School of the Environment, Duke University, Durham, NC.
⁵¹ Department of Medicine, University of California San Francisco, San Francisco, Calif; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, Calif.
⁵² Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Pediatric Allergy and Pulmonology Unit at Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
⁵³ Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
⁵⁴ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Sachs' Children's Hospital, Södersjukhuset, Stockholm, Sweden.
⁵⁵ Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Pediatrics, Division of Neonatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁵⁶ Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁵⁷ Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC. Electronic address: london2@niehs.nih.gov.

PMID: 30579849
PMCID: PMC6556405
DOI: 10.1016/j.jaci.2018.11.043

Meta-Analysis

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

Sarah E Reese et al. J Allergy Clin Immunol. 2019 Jun.

. 2019 Jun;143(6):2062-2074.

doi: 10.1016/j.jaci.2018.11.043. Epub 2018 Dec 21.

Authors

Affiliations

¹ Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC.
² Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
³ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁴ CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; ISGlobal, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
⁵ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁶ Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
⁷ Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway; Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway.
⁸ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁹ Curtin/UWA Centre for Genetic Origins of Health and Disease, Faculty of Health and Medical Sciences, University of Western Australia, Crawley, Australia; School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Australia.
¹⁰ Department of Medicine, University of California San Francisco, San Francisco, Calif.
¹¹ Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colo.
¹² Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
¹³ Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
¹⁴ Bioinformatics Research Center, North Carolina State University, Raleigh, NC; Center for Human Health and the Environment, North Carolina State University, Raleigh, NC.
¹⁵ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
¹⁶ Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
¹⁷ Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹⁸ Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, United Kingdom.
¹⁹ Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, Ludwig-Maximilians Universität München (LMU), Munich, Germany.
²⁰ Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland; Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland.
²¹ Centre intégré universitaire de santé et de services sociaux du Saguenay, Saguenay, Quebec, Canada; Département des sciences fondamentales, Université du Québec à Chicoutimi, Saguenay, Quebec, Canada.
²² Département des sciences fondamentales, Université du Québec à Chicoutimi, Saguenay, Quebec, Canada.
²³ GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
²⁴ Division of Mental and Physical Health, Norwegian Institute of Public Health, Oslo, Norway.
²⁵ Telethon Kids Institute, University of Western Australia, Perth, Australia.
²⁶ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.
²⁷ Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; Bristol Dental School, University of Bristol, Bristol, United Kingdom.
²⁸ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
²⁹ CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; ISGlobal, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Barcelona, Spain.
³⁰ Department of Biological Sciences, North Carolina State University, Raleigh, NC; Department of Community and Family Medicine, Duke University Medical Center, Durham, NC.
³¹ Epidemiology of Allergic and Respiratory Diseases Department, IPLESP, INSERM and UPMC Sorbonne Université, Paris, France.
³² Research Unit for Gynaecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
³³ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
³⁴ Biocenter Oulu, University of Oulu, Oulu, Finland; Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland; Department of Genomics of Complex Diseases, School of Public Health, Imperial College London, London, United Kingdom.
³⁵ Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, Memphis, Tenn.
³⁶ Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland; Department of Obstetrics and Gynaecology, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland; Hospital for Children and Adolescents, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
³⁷ Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; Division of Mental and Physical Health, Norwegian Institute of Public Health, Oslo, Norway.
³⁸ Children's Hospital Colorado, Aurora, Colo.
³⁹ Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; Sachs' Children's Hospital, Södersjukhuset, Stockholm, Sweden.
⁴⁰ CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; ISGlobal, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
⁴¹ Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden; Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
⁴² Center for Human Health and the Environment, North Carolina State University, Raleigh, NC; Department of Biological Sciences, North Carolina State University, Raleigh, NC.
⁴³ Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; David Hide Asthma and Allergy Research Centre, Isle of Wight, United Kingdom.
⁴⁴ Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
⁴⁵ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Ga; Max-Planck-Institute of Psychiatry, Munich, Germany.
⁴⁶ Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland.
⁴⁷ Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum Muenchen, Munich, Germany.
⁴⁸ Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
⁴⁹ Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, United Kingdom; Biocenter Oulu, University of Oulu, Oulu, Finland; Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
⁵⁰ Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC; Nicholas School of the Environment, Duke University, Durham, NC.
⁵¹ Department of Medicine, University of California San Francisco, San Francisco, Calif; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, Calif.
⁵² Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Pediatric Allergy and Pulmonology Unit at Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
⁵³ Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
⁵⁴ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Sachs' Children's Hospital, Södersjukhuset, Stockholm, Sweden.
⁵⁵ Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Pediatrics, Division of Neonatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁵⁶ Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁵⁷ Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC. Electronic address: london2@niehs.nih.gov.

PMID: 30579849
PMCID: PMC6556405
DOI: 10.1016/j.jaci.2018.11.043

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.

Published by Elsevier Inc.

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Conflict of interest statement

Disclosure of potential conflict of interest: C. Ruiz-Arenas receives grant support from Agència de Gestió d’Ajuts Universitaris i de Recerca. S. S. Oh, C. Eng, and E. G. Burchard receive grant support from the NIH and the Tobacco-Related Disease Research Program. I. V. Yang and C. V. Breton receive grant support from the National Institutes of Health (NIH). C. Söderhäll receives grant support from several competitive grants from public and private sources and receives royalties from book chapters in study material. R. Arathimos and G. C. Sharp receive support from the Medical Research Council. E. Kajantie receives grant support from the European Commission, Academy of Finland, Foundation for Pediatric Research, Sigrid Jus×lius Foundation, Signe and Ane Gyllenberg Foundation, and Juho Vainio Foundation. G. Pershagen receives grant support from the Swedish Research Council. C. L. Relton receives grant support from Wellcome Trust. C. Almqvist receives grant support from the Swedish Research Council through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM) framework, Stockholm County Council (ALF-projects), Swedish Heart-Lung Foundation, and Swedish Asthma and Allergy Association’s Research Foundation. A. J. Henderson receives grant support from the Medical Research Council and Wellcome Trust. E. Melén received grant support from the European Research Council during conduct of the study and lecture fees from Thermo Fisher Scientific and Meda outside the submitted work. G. H. Koppelman receives grant support from the Lung Foundation of the Netherlands, MEDALL EU FP7, the UBBO EMMIUS Foundation, TEVA The Netherlands, Vertex, GlaxoSmithKline, and the TETRI Foundation. The rest of the authors declare that they have no relevant conflicts of interest.

Figures

**FIG 1.**
Meta-analysis of asthma in relation to newborn methylation: A, Manhattan plot; B, volcano plot. The model is adjusted for covariates and cell types.

**FIG 2.**
Meta-analysis of asthma in relation to childhood methylation: A, Manhattan plot; B, volcano plot. The model is adjusted for covariates and cell types. CpGs corresponding to more than 1 gene with significant CpGs (FDR < 0.05) are highlighted in red.

**FIG 3.**
A network is shown for 4 categories of disease and biological functions overlapping between analyses of asthma in relation to either newborn or childhood methylation: immunological disease, cell-mediated immune response, inflammatory disease, and tissue morphology. A gene is connected to a disease or function if it has been previously shown to be involved in it. All genes marked in red are implicated from newborn methylation analyses, and those marked in in orange are implicated from childhood methylation analyses.

See this image and copyright information in PMC

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

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

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