Meta-Analysis

. 2019 Apr 23;10(1):1893.

doi: 10.1038/s41467-019-09671-3.

Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight

Leanne K Küpers^{1

2

3

4}, Claire Monnereau^{5

6

7}, Gemma C Sharp^{1

8}, Paul Yousefi^{1

2

9}, Lucas A Salas^{10

11}, Akram Ghantous¹², Christian M Page^{13

14}, Sarah E Reese¹⁵, Allen J Wilcox¹⁵, Darina Czamara¹⁶, Anne P Starling¹⁷, Alexei Novoloaca¹², Samantha Lent¹⁸, Ritu Roy^{19

20}, Cathrine Hoyo^{21

22}, Carrie V Breton²³, Catherine Allard²⁴, Allan C Just²⁵, Kelly M Bakulski²⁶, John W Holloway^{27

28}, Todd M Everson²⁹, Cheng-Jian Xu^{30

31}, Rae-Chi Huang³², Diana A van der Plaat³³, Matthias Wielscher³⁴, Simon Kebede Merid³⁵, Vilhelmina Ullemar³⁶, Faisal I Rezwan²⁸, Jari Lahti^{37

38}, Jenny van Dongen³⁹, Sabine A S Langie^{40

41

42}, Tom G Richardson^{1

2}, Maria C Magnus^{1

2

13}, Ellen A Nohr⁴³, Zongli Xu⁴⁴, Liesbeth Duijts^{4

44

45}, Shanshan Zhao⁴⁶, Weiming Zhang⁴⁷, Michelle Plusquin^{48

49}, Dawn L DeMeo⁵⁰, Olivia Solomon⁸, Joosje H Heimovaara³, Dereje D Jima^{22

51}, Lu Gao²³, Mariona Bustamante^{11

52

53

54}, Patrice Perron^{24

55}, Robert O Wright²⁵, Irva Hertz-Picciotto⁵⁶, Hongmei Zhang⁵⁷, Margaret R Karagas^{10

58}, Ulrike Gehring⁵⁹, Carmen J Marsit²⁹, Lawrence J Beilin⁶⁰, Judith M Vonk³³, Marjo-Riitta Jarvelin^{34

61

62

63}, Anna Bergström^{35

64}, Anne K Örtqvist³⁶, Susan Ewart⁶⁵, Pia M Villa⁶⁶, Sophie E Moore^{67

68}, Gonneke Willemsen³⁹, Arnout R L Standaert⁴⁰, Siri E Håberg¹³, Thorkild I A Sørensen^{1

69

70}, Jack A Taylor¹⁵, Katri Räikkönen³⁸, Ivana V Yang⁷¹, Katerina Kechris⁴⁵, Tim S Nawrot^{48

72}, Matt J Silver⁶⁷, Yun Yun Gong⁷³, Lorenzo Richiardi^{74

75}, Manolis Kogevinas^{11

53

54

76}, Augusto A Litonjua⁵⁰, Brenda Eskenazi^{9

77}, Karen Huen⁹, Hamdi Mbarek⁷⁸, Rachel L Maguire^{21

79}, Terence Dwyer⁸⁰, Martine Vrijheid^{11

53

54}, Luigi Bouchard^{81

82}, Andrea A Baccarelli^{83

84}, Lisa A Croen⁸⁵, Wilfried Karmaus⁵⁷, Denise Anderson³², Maaike de Vries³³, Sylvain Sebert^{61

62

86}, Juha Kere^{87

88

89}, Robert Karlsson³⁶, Syed Hasan Arshad^{27

90}, Esa Hämäläinen⁹¹, Michael N Routledge⁹², Dorret I Boomsma^{39

93}, Andrew P Feinberg⁹⁴, Craig J Newschaffer⁹⁵, Eva Govarts⁴⁰, Matthieu Moisse^{96

97}, M Daniele Fallin⁹⁸, Erik Melén^{35

99}, Andrew M Prentice⁶⁷, Eero Kajantie^{100

101

102}, Catarina Almqvist^{36

103}, Emily Oken¹⁰⁴, Dana Dabelea¹⁰⁵, H Marike Boezen³³, Phillip E Melton^{106

107}, Rosalind J Wright²⁵, Gerard H Koppelman³⁰, Letizia Trevisi¹⁰⁸, Marie-France Hivert^{55

104

109}, Jordi Sunyer^{11

53

54

76}, Monica C Munthe-Kaas^{110

111}, Susan K Murphy¹¹², Eva Corpeleijn³, Joseph Wiemels¹¹³, Nina Holland⁹, Zdenko Herceg¹², Elisabeth B Binder^{16

114}, George Davey Smith^{1

2}, Vincent W V Jaddoe^{5

6

7}, Rolv T Lie^{13

115}, Wenche Nystad¹¹⁶, Stephanie J London¹⁵, Debbie A Lawlor^{117

118}, Caroline L Relton^{119

120}, Harold Snieder¹²¹, Janine F Felix^{122

123

124}

Affiliations

¹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
² Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
³ University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands.
⁴ Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands.
⁵ The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁶ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁷ Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁸ School of Oral and Dental Sciences, University of Bristol, Bristol, UK.
⁹ Children's Environmental Health Laboratory, Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, USA.
¹⁰ Department of Epidemiology, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA.
¹¹ ISGlobal, Bacelona Institute for Global Health, Barcelona, Spain.
¹² Epigenetics Group, International Agency for Research on Cancer, Lyon, France.
¹³ Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
¹⁴ Oslo Centre for Biostatisitcs and Epidemology, Oslo University Hospital, Oslo, Norway.
¹⁵ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Service, Research Triangle Park, Durham, NC, USA.
¹⁶ Department of Translational Research in Psychiatry, Max-Planck-Institute of Psychiatry, Munich, Germany.
¹⁷ Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹⁸ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹⁹ HDF Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
²⁰ Computational Biology and Informatics, UCSF, San Francisco, CA, USA.
²¹ Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.
²² Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, USA.
²³ Department of Preventive Medicine, University of Southern California, Los Angeles, CA, 90089, USA.
²⁴ Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Sherbrooke, QC, Canada.
²⁵ Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁶ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
²⁷ Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
²⁸ Human Development and Health, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
²⁹ Department of Environmental Health, Rollins School of Public Health at Emory University, Atlanta, GA, USA.
³⁰ University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands.
³¹ University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
³² Telethon Kids Institute, University of Western Australia, Perth, Australia.
³³ University of Groningen, University Medical Center Groningen, Department of Epidemiology and Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands.
³⁴ Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, UK.
³⁵ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
³⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
³⁷ Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland.
³⁸ Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
³⁹ Department of Biological Psychology, Netherlands Twin Register, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁴⁰ VITO - Health, Mol, Belgium.
⁴¹ Theoretical Physics, Faculty of Sciences, Hasselt University, Hasselt, Belgium.
⁴² Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium.
⁴³ Research Unit for Gynaecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
⁴⁴ Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁴⁵ Department of Pediatrics, Division of Neonatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁴⁶ Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, Durham, NC, USA.
⁴⁷ Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁴⁸ Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium.
⁴⁹ MRC/PHE Centre for Environment and Health School of Public Health Imperial College London, St Mary's Campus, Norfolk Place, London, UK.
⁵⁰ Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁵¹ Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA.
⁵² Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), Barcelona, Spain.
⁵³ Universitat Pompeu Fabra (UPF), Barcelona, Spain.
⁵⁴ CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.
⁵⁵ Department of Medicine, Universite de Sherbrooke, Sherbrooke, QC, Canada.
⁵⁶ Department of Public Health Sciences, School of Medicine, University of California Davis MIND Institute, Sacramento, CA, USA.
⁵⁷ Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA.
⁵⁸ Children's Environmental Health & Disease Prevention Research Center at Dartmouth, Hanover, NH, USA.
⁵⁹ Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands.
⁶⁰ Medical School, University of Western Australia, Perth, Australia.
⁶¹ Center for Life Course Health Research, Faculty of Medicine, University of Oulu, 90014, Oulu, Finland.
⁶² Biocenter Oulu, University of Oulu, Oulu, Finland.
⁶³ Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
⁶⁴ Center for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.
⁶⁵ College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA.
⁶⁶ Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁶⁷ Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, London, UK.
⁶⁸ Department of Women and Children's Health, King's College London, London, UK.
⁶⁹ Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷⁰ Department of Public Health, Section of Epidemiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷¹ Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁷² Department of Public Health & Primary Care, Leuven University, Leuven, Belgium.
⁷³ School of Food Sciences and Nutrition, University of Leeds, Leeds, UK.
⁷⁴ Department of Medical Sciences, University of Turin, Turin, Italy.
⁷⁵ AOU Citta della Salute e della Sceinza, CPO Piemonte, Turin, Italy.
⁷⁶ IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
⁷⁷ Center for Environmental Research and Children's Health, School of Public Health, University of California, Berkeley, CA, USA.
⁷⁸ Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁷⁹ Department of Community and Family Medicine, Duke University Medical Center, Raleigh, NC, USA.
⁸⁰ The George Institute for Global Health, Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, UK.
⁸¹ Department of Biochemistry, Université de Sherbrooke, Sherbrooke, QC, Canada.
⁸² ECOGENE-21 Biocluster, Chicoutimi Hospital, Saguenay, QC, Canada.
⁸³ Laboratory of Precision Environmental Biosciences, Columbia University Mailman School of Public Health, New York, NY, USA.
⁸⁴ Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA.
⁸⁵ Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
⁸⁶ Department for Genomics of Common Diseases, School of Public Health, Imperial College London, London, UK.
⁸⁷ Folkhälsan Institute of Genetics, Helsinki, and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
⁸⁸ Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
⁸⁹ School of Basic and Medical Biosciences, King's College London, Guy's Hospital, London, UK.
⁹⁰ David Hide Asthma and Allergy Research Centre, Isle of Wight, UK.
⁹¹ HUSLAB and the Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland.
⁹² LICAMM, School of Medicine, Univeristy of Leeds, Leeds, UK.
⁹³ Amsterdam Public Health Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁹⁴ Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MA, USA.
⁹⁵ AJ Drexel Autism Institute, Drexel University, Philadelphia, PA, USA.
⁹⁶ KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND), Leuven, Belgium.
⁹⁷ VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium.
⁹⁸ Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
⁹⁹ Sachs' Children's Hospital, Stockholm, Sweden.
¹⁰⁰ National Institute for Health and Welfare, Helsinki and Oulu, Oulu, Finland.
¹⁰¹ Hospital for Children and Adolescents, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
¹⁰² PEDEGO Research Unit, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
¹⁰³ Pediatric Allergy and Pulmonology Unit at Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
¹⁰⁴ Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, MA, USA.
¹⁰⁵ Department of Epidemiology, Colorado School of Public Health, and Department of Pediatrics, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹⁰⁶ Centre for Genetic Origins of Health and Disease, School of Biomedical Sciences, University of Western Australia, Perth, Australia.
¹⁰⁷ School of Pharmacy and Biomedical Sciences, Curtin University, Perth, Australia.
¹⁰⁸ Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA.
¹⁰⁹ Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
¹¹⁰ Norwegian Institute of Public Health, Oslo, Norway.
¹¹¹ Department of Pediatric Oncology and Hematology, Oslo University Hospital, Oslo, Norway.
¹¹² Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA.
¹¹³ Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
¹¹⁴ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Altanta, GA, USA.
¹¹⁵ Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
¹¹⁶ Department for Non-Communicable Diseases, Norwegian Institute for Public Health, Oslo, Norway.
¹¹⁷ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. d.a.Lawlor@bristol.ac.uk.
¹¹⁸ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. d.a.Lawlor@bristol.ac.uk.
¹¹⁹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. caroline.relton@bristol.ac.uk.
¹²⁰ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. caroline.relton@bristol.ac.uk.
¹²¹ University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands. h.snieder@umcg.nl.
¹²² The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. j.felix@erasmusmc.nl.
¹²³ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. j.felix@erasmusmc.nl.
¹²⁴ Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. j.felix@erasmusmc.nl.

PMID: 31015461
PMCID: PMC6478731
DOI: 10.1038/s41467-019-09671-3

Meta-Analysis

Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight

Leanne K Küpers et al. Nat Commun. 2019.

. 2019 Apr 23;10(1):1893.

doi: 10.1038/s41467-019-09671-3.

Authors

Affiliations

¹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
² Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
³ University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands.
⁴ Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands.
⁵ The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁶ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁷ Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁸ School of Oral and Dental Sciences, University of Bristol, Bristol, UK.
⁹ Children's Environmental Health Laboratory, Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, USA.
¹⁰ Department of Epidemiology, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA.
¹¹ ISGlobal, Bacelona Institute for Global Health, Barcelona, Spain.
¹² Epigenetics Group, International Agency for Research on Cancer, Lyon, France.
¹³ Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
¹⁴ Oslo Centre for Biostatisitcs and Epidemology, Oslo University Hospital, Oslo, Norway.
¹⁵ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Service, Research Triangle Park, Durham, NC, USA.
¹⁶ Department of Translational Research in Psychiatry, Max-Planck-Institute of Psychiatry, Munich, Germany.
¹⁷ Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹⁸ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹⁹ HDF Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
²⁰ Computational Biology and Informatics, UCSF, San Francisco, CA, USA.
²¹ Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.
²² Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, USA.
²³ Department of Preventive Medicine, University of Southern California, Los Angeles, CA, 90089, USA.
²⁴ Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Sherbrooke, QC, Canada.
²⁵ Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁶ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
²⁷ Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
²⁸ Human Development and Health, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
²⁹ Department of Environmental Health, Rollins School of Public Health at Emory University, Atlanta, GA, USA.
³⁰ University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands.
³¹ University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
³² Telethon Kids Institute, University of Western Australia, Perth, Australia.
³³ University of Groningen, University Medical Center Groningen, Department of Epidemiology and Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands.
³⁴ Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, UK.
³⁵ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
³⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
³⁷ Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland.
³⁸ Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
³⁹ Department of Biological Psychology, Netherlands Twin Register, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁴⁰ VITO - Health, Mol, Belgium.
⁴¹ Theoretical Physics, Faculty of Sciences, Hasselt University, Hasselt, Belgium.
⁴² Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium.
⁴³ Research Unit for Gynaecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
⁴⁴ Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁴⁵ Department of Pediatrics, Division of Neonatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁴⁶ Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, Durham, NC, USA.
⁴⁷ Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁴⁸ Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium.
⁴⁹ MRC/PHE Centre for Environment and Health School of Public Health Imperial College London, St Mary's Campus, Norfolk Place, London, UK.
⁵⁰ Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁵¹ Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA.
⁵² Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), Barcelona, Spain.
⁵³ Universitat Pompeu Fabra (UPF), Barcelona, Spain.
⁵⁴ CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.
⁵⁵ Department of Medicine, Universite de Sherbrooke, Sherbrooke, QC, Canada.
⁵⁶ Department of Public Health Sciences, School of Medicine, University of California Davis MIND Institute, Sacramento, CA, USA.
⁵⁷ Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA.
⁵⁸ Children's Environmental Health & Disease Prevention Research Center at Dartmouth, Hanover, NH, USA.
⁵⁹ Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands.
⁶⁰ Medical School, University of Western Australia, Perth, Australia.
⁶¹ Center for Life Course Health Research, Faculty of Medicine, University of Oulu, 90014, Oulu, Finland.
⁶² Biocenter Oulu, University of Oulu, Oulu, Finland.
⁶³ Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
⁶⁴ Center for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.
⁶⁵ College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA.
⁶⁶ Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁶⁷ Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, London, UK.
⁶⁸ Department of Women and Children's Health, King's College London, London, UK.
⁶⁹ Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷⁰ Department of Public Health, Section of Epidemiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷¹ Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁷² Department of Public Health & Primary Care, Leuven University, Leuven, Belgium.
⁷³ School of Food Sciences and Nutrition, University of Leeds, Leeds, UK.
⁷⁴ Department of Medical Sciences, University of Turin, Turin, Italy.
⁷⁵ AOU Citta della Salute e della Sceinza, CPO Piemonte, Turin, Italy.
⁷⁶ IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
⁷⁷ Center for Environmental Research and Children's Health, School of Public Health, University of California, Berkeley, CA, USA.
⁷⁸ Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁷⁹ Department of Community and Family Medicine, Duke University Medical Center, Raleigh, NC, USA.
⁸⁰ The George Institute for Global Health, Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, UK.
⁸¹ Department of Biochemistry, Université de Sherbrooke, Sherbrooke, QC, Canada.
⁸² ECOGENE-21 Biocluster, Chicoutimi Hospital, Saguenay, QC, Canada.
⁸³ Laboratory of Precision Environmental Biosciences, Columbia University Mailman School of Public Health, New York, NY, USA.
⁸⁴ Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA.
⁸⁵ Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
⁸⁶ Department for Genomics of Common Diseases, School of Public Health, Imperial College London, London, UK.
⁸⁷ Folkhälsan Institute of Genetics, Helsinki, and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
⁸⁸ Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
⁸⁹ School of Basic and Medical Biosciences, King's College London, Guy's Hospital, London, UK.
⁹⁰ David Hide Asthma and Allergy Research Centre, Isle of Wight, UK.
⁹¹ HUSLAB and the Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland.
⁹² LICAMM, School of Medicine, Univeristy of Leeds, Leeds, UK.
⁹³ Amsterdam Public Health Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁹⁴ Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MA, USA.
⁹⁵ AJ Drexel Autism Institute, Drexel University, Philadelphia, PA, USA.
⁹⁶ KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND), Leuven, Belgium.
⁹⁷ VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium.
⁹⁸ Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
⁹⁹ Sachs' Children's Hospital, Stockholm, Sweden.
¹⁰⁰ National Institute for Health and Welfare, Helsinki and Oulu, Oulu, Finland.
¹⁰¹ Hospital for Children and Adolescents, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
¹⁰² PEDEGO Research Unit, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
¹⁰³ Pediatric Allergy and Pulmonology Unit at Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
¹⁰⁴ Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, MA, USA.
¹⁰⁵ Department of Epidemiology, Colorado School of Public Health, and Department of Pediatrics, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹⁰⁶ Centre for Genetic Origins of Health and Disease, School of Biomedical Sciences, University of Western Australia, Perth, Australia.
¹⁰⁷ School of Pharmacy and Biomedical Sciences, Curtin University, Perth, Australia.
¹⁰⁸ Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA.
¹⁰⁹ Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
¹¹⁰ Norwegian Institute of Public Health, Oslo, Norway.
¹¹¹ Department of Pediatric Oncology and Hematology, Oslo University Hospital, Oslo, Norway.
¹¹² Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA.
¹¹³ Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
¹¹⁴ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Altanta, GA, USA.
¹¹⁵ Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
¹¹⁶ Department for Non-Communicable Diseases, Norwegian Institute for Public Health, Oslo, Norway.
¹¹⁷ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. d.a.Lawlor@bristol.ac.uk.
¹¹⁸ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. d.a.Lawlor@bristol.ac.uk.
¹¹⁹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. caroline.relton@bristol.ac.uk.
¹²⁰ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. caroline.relton@bristol.ac.uk.
¹²¹ University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands. h.snieder@umcg.nl.
¹²² The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. j.felix@erasmusmc.nl.
¹²³ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. j.felix@erasmusmc.nl.
¹²⁴ Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. j.felix@erasmusmc.nl.

PMID: 31015461
PMCID: PMC6478731
DOI: 10.1038/s41467-019-09671-3

Abstract

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (P_Bonferroni < 1.06 x 10^-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10^-74) and BMI in pregnancy (3/914, p = 1.13x10^-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1**
Hypothetical paths that might link intrauterine exposures to DNA methylation, birthweight and later-life health outcomes. Red arrows summarise the paths that have motivated the analyses undertaken in this study (i.e. that maternal environmental exposures influence DNA methylation that in turn influences fetal growth and hence birthweight). The EWAS meta-analysis undertaken sought to identify methylation associated with birthweight. Blue arrows summarise other plausible paths, including that maternal exposures influence fetal growth first and it then influences DNA methylation or that maternal exposures may influence fetal growth/birthweight and later-life health outcomes through other pathways than DNA methylation

**Fig. 2**
Design of the study. Schematic representation of the main meta-analysis, secondary meta-analyses, follow-up analyses and exploration of persistence at older ages. *We removed multiple births from all analyses and excluded preterm births (<37 weeks) and offspring of mothers with pre-eclampsia or diabetes (three major pathological causes of differences). **For sufficient power in the low vs normal BW analyses, we only included nine studies with >10 low birthweight cases

**Fig. 3**
Volcano plot showing the direction of associations of DNA methylation with birthweight in 8825 neonates from 24 studies. The X-axis represents the difference in birthweight in grams per 10% methylation difference, the Y-axis represents the −log₁₀(P). The red line shows the Bonferroni-corrected significance threshold for multiple testing (p < 1.06 × 10⁻⁷). Highlighted in orange are the 914 CpGs with p < 1.06 × 10⁻⁷ and I² ≤ 50% and highlighted in blue are the 115 CpGs with p < 1.06 × 10⁻⁷ and I² > 50%

**Fig. 4**
Circos plot showing the (Bonferroni-corrected p < 1.06 × 10⁻⁷) results for associations of DNA methylation with birthweight. Results are presented as CpG-specific associations (−log₁₀(P), each dot represents a CpG) by genomic position, per chromosome. From outer to inner track: [1, orange] Main analysis results for associations between DNA methylation and birthweight as a continuous measure (n = 8825), [2, blue] Results from participants from European ethnicity only, DNA methylation and birthweight as a continuous measure (n = 6023), [3, red] Results from analysis without exclusion for preterm births, pre-eclampsia and maternal diabetes, DNA methylation and birthweight as a continuous measure n = 5414), [4, purple] Results from logistic regression analysis without exclusion for preterm births, pre-eclampsia and maternal diabetes, for low (n = 178) vs normal (n = 4197) birthweight, [5, yellow] Results from logistic regression analysis for associations between DNA methylation and high (n = 1590) vs normal (n = 6114) birthweight, [6, green] Results from look-up analysis in methylation samples taken during childhood and its association with birthweight as a continuous measure (n = 2756). Track 1: highlighted in red are 115 CpGs with I² > 50%. Tracks 2–6: highlighted in red are CpGs that were not found in the 914 main meta-analysis hits (though note differences in sample size and hence statistical power for different analyses presented in the different tracks)

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Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight

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Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight

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