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Nat Commun. 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.

Küpers LK1,2,3,4, Monnereau C5,6,7, Sharp GC1,8, Yousefi P1,2,9, Salas LA10,11, Ghantous A12, Page CM13,14, Reese SE15, Wilcox AJ15, Czamara D16, Starling AP17, Novoloaca A12, Lent S18, Roy R19,20, Hoyo C21,22, Breton CV23, Allard C24, Just AC25, Bakulski KM26, Holloway JW27,28, Everson TM29, Xu CJ30,31, Huang RC32, van der Plaat DA33, Wielscher M34, Merid SK35, Ullemar V36, Rezwan FI28, Lahti J37,38, van Dongen J39, Langie SAS40,41,42, Richardson TG1,2, Magnus MC1,2,13, Nohr EA43, Xu Z44, Duijts L4,44,45, Zhao S46, Zhang W47, Plusquin M48,49, DeMeo DL50, Solomon O8, Heimovaara JH3, Jima DD22,51, Gao L23, Bustamante M11,52,53,54, Perron P24,55, Wright RO25, Hertz-Picciotto I56, Zhang H57, Karagas MR10,58, Gehring U59, Marsit CJ29, Beilin LJ60, Vonk JM33, Jarvelin MR34,61,62,63, Bergström A35,64, Örtqvist AK36, Ewart S65, Villa PM66, Moore SE67,68, Willemsen G39, Standaert ARL40, Håberg SE13, Sørensen TIA1,69,70, Taylor JA15, Räikkönen K38, Yang IV71, Kechris K45, Nawrot TS48,72, Silver MJ67, Gong YY73, Richiardi L74,75, Kogevinas M11,53,54,76, Litonjua AA50, Eskenazi B9,77, Huen K9, Mbarek H78, Maguire RL21,79, Dwyer T80, Vrijheid M11,53,54, Bouchard L81,82, Baccarelli AA83,84, Croen LA85, Karmaus W57, Anderson D32, de Vries M33, Sebert S61,62,86, Kere J87,88,89, Karlsson R36, Arshad SH27,90, Hämäläinen E91, Routledge MN92, Boomsma DI39,93, Feinberg AP94, Newschaffer CJ95, Govarts E40, Moisse M96,97, Fallin MD98, Melén E35,99, Prentice AM67, Kajantie E100,101,102, Almqvist C36,103, Oken E104, Dabelea D105, Boezen HM33, Melton PE106,107, Wright RJ25, Koppelman GH30, Trevisi L108, Hivert MF55,104,109, Sunyer J11,53,54,76, Munthe-Kaas MC110,111, Murphy SK112, Corpeleijn E3, Wiemels J113, Holland N9, Herceg Z12, Binder EB16,114, Davey Smith G1,2, Jaddoe VWV5,6,7, Lie RT13,115, Nystad W116, London SJ15, Lawlor DA117,118, Relton CL119,120, Snieder H121, Felix JF122,123,124.

Author information

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.

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 (PBonferroni < 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.

PMID:
31015461
PMCID:
PMC6478731
DOI:
10.1038/s41467-019-09671-3
[Indexed for MEDLINE]
Free PMC Article

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