Meta-Analysis

. 2017 Oct 15;26(20):4067-4085.

doi: 10.1093/hmg/ddx290.

Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium

Gemma C Sharp^{1

2

3}, Lucas A Salas^{4

5

6}, Claire Monnereau^{7

8

9}, Catherine Allard¹⁰, Paul Yousefi¹¹, Todd M Everson¹², Jon Bohlin¹³, Zongli Xu¹⁴, Rae-Chi Huang¹⁵, Sarah E Reese¹⁶, Cheng-Jian Xu^{17

18}, Nour Baïz¹⁹, Cathrine Hoyo^{20

21}, Golareh Agha²², Ritu Roy^{23

24

25}, John W Holloway²⁶, Akram Ghantous²⁷, Simon K Merid²⁸, Kelly M Bakulski²⁹, Leanne K Küpers^{1

2

30}, Hongmei Zhang³¹, Rebecca C Richmond^{1

2}, Christian M Page³², Liesbeth Duijts^{7

9}, Rolv T Lie^{33

34}, Phillip E Melton^{35

36}, Judith M Vonk³⁷, Ellen A Nohr³⁸, ClarLynda Williams-DeVane³⁹, Karen Huen¹¹, Sheryl L Rifas-Shiman⁴⁰, Carlos Ruiz-Arenas^{4

6

41}, Semira Gonseth^{42

43}, Faisal I Rezwan²⁶, Zdenko Herceg²⁷, Sandra Ekström²⁸, Lisa Croen⁴⁴, Fahimeh Falahi³⁰, Patrice Perron^{10

45}, Margaret R Karagas^{46

47}, Bilal M Quraishi³¹, Matthew Suderman^{1

2}, Maria C Magnus^{1

2

32}, Vincent W V Jaddoe^{7

8

9}, Jack A Taylor^{14

48}, Denise Anderson¹⁵, Shanshan Zhao¹⁶, Henriette A Smit⁴⁹, Michele J Josey^{39

50}, Asa Bradman¹¹, Andrea A Baccarelli²², Mariona Bustamante^{4

6

51}, Siri E Håberg⁵², Göran Pershagen^{28

53}, Irva Hertz-Picciotto⁵⁴, Craig Newschaffer⁵⁵, Eva Corpeleijn³⁰, Luigi Bouchard^{56

57}, Debbie A Lawlor^{1

2}, Rachel L Maguire^{20

58}, Lisa F Barcellos¹¹, George Davey Smith^{1

2}, Brenda Eskenazi¹¹, Wilfried Karmaus³⁰, Carmen J Marsit¹², Marie-France Hivert^{40

45

59}, Harold Snieder³⁰, M Daniele Fallin⁶⁰, Erik Melén^{28

53

61}, Monica C Munthe-Kaas^{62

63}, Hasan Arshad^{64

65

66}, Joseph L Wiemels⁴², Isabella Annesi-Maesano¹⁹, Martine Vrijheid^{4

6

41}, Emily Oken⁴⁰, Nina Holland¹¹, Susan K Murphy⁶⁷, Thorkild I A Sørensen^{1

68

69}, Gerard H Koppelman⁷⁰, John P Newnham⁷¹, Allen J Wilcox¹⁴, Wenche Nystad³², Stephanie J London¹⁶, Janine F Felix^{7

8

9}, Caroline L Relton^{1

2}

Affiliations

¹ MRC Integrative Epidemiology Unit.
² School of Social and Community Medicine.
³ School of Oral and Dental Sciences, University of Bristol, Bristol, UK.
⁴ ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
⁵ Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
⁶ Universitat Pompeu Fabra (UPF), Barcelona, Spain.
⁷ The Generation R Study Group.
⁸ Department of Epidemiology.
⁹ Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹⁰ Centre de Recherche du Centre Hospitalier, Université de Sherbrooke, QC, Canada.
¹¹ Center for Environmental Research and Children's Health (CERCH), School of Public Health, University of California Berkeley.
¹² Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
¹³ Department of Infection Epidemiology and Modeling, Norwegian Institute of Public Health, Oslo, Norway.
¹⁴ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA.
¹⁵ Telethon Kids Institute, University of Western Australia, Crawley, WA 6009, Australia.
¹⁶ National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA.
¹⁷ Department of Pulmonology, GRIAC Research Institute.
¹⁸ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹⁹ Epidemiology of Allergic and Respiratory Diseases Department (EPAR), Sorbonne Université, UPMC Univ Paris 06, INSERM, Pierre Louis Institute of Epidemiology and Public Health, Saint-Antoine Medical School, Paris, France.
²⁰ Department of Biological Sciences.
²¹ Center for Human Health and the Environment, North Carolina State University, NC, USA.
²² Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA.
²³ University of California San Francisco, CA, USA.
²⁴ HDF Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
²⁵ Computational Biology Core.
²⁶ Human Development & Health, Faculty of Medicine, University of Southampton, UK.
²⁷ Epigenetics Group, International Agency for Research on Cancer, Lyon, France.
²⁸ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
²⁹ Department of Epidemiology, School of Public Health, University of Michigan, MI, USA.
³⁰ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
³¹ Division of Epidemiology, Biostatistics, and Environmental Health Sciences, School of Public Health, University of Memphis, Memphis, TN, USA.
³² Department of Non-Communicable Disease, Norwegian Institute of Public Health, Oslo, Norway.
³³ Department of Global Public Health and Primary Care, University of Bergen, Norway.
³⁴ Medical Birth Registry of Norway, Norwegian Institute of Public Health, Bergen, Norway.
³⁵ The Curtin UWA Centre for Genetic Origins of Health and Disease, Faculty of Health Sciences, Curtin University Health Sciences, Curtin University and Faculty of Medicine Dentistry & Health Sciences, The University of Western Australia, Perth, Australia.
³⁶ Faculty of Medicine Dentistry & Health Sciences, The University of Western Australia, Perth, Australia.
³⁷ Department of Epidemiology, University of Groningen, University Medical Center Groningen, GRIAC Research Institute Groningen, The Netherlands.
³⁸ Research Unit for Gynaecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
³⁹ Department of Biological & Biomedical Sciences, North Carolina Central University, Durham, NC, USA.
⁴⁰ Obesity Prevention Program, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, USA.
⁴¹ CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.
⁴² Department of Epidemiology and Biostatistics, University of California San Francisco, CA, USA.
⁴³ School of Public Health, University of California Berkeley, CA, USA.
⁴⁴ Division of Research, Kaiser Permanente Northern California, CA, UDA.
⁴⁵ Department of Medicine, Université de Sherbrooke, QC, Canada.
⁴⁶ Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
⁴⁷ Children's Environmental Health & Disease Prevention Research Center at Dartmouth, Hanover, NH, USA.
⁴⁸ Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
⁴⁹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands.
⁵⁰ Epidemiology and Biostatistics Department, University of South Carolina (Columbia), SC, USA.
⁵¹ Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
⁵² Domain of Mental and Physical Health, Norwegian Institute of Public Health, Oslo, Norway.
⁵³ Center for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.
⁵⁴ Department of Public Health, School of Medicine, University of California, Davis, CA, USA.
⁵⁵ AJ Drexel Autism Institute, Drexel University, Philadelphia, PA, USA.
⁵⁶ Department of Biochemistry, Université de Sherbrooke, QC, Canada.
⁵⁷ ECOGENE-21 and Lipid Clinic, Chicoutimi Hospital, Saguenay, QC, Canada.
⁵⁸ Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA.
⁵⁹ Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
⁶⁰ Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
⁶¹ Sachs' Children's Hospital, South General Hospital, Stockholm, Sweden.
⁶² Department of Pediatric and Adolescent Medicine, Oslo University Hospital, Norway.
⁶³ Norwegian Institute of Public Health, Oslo Norway.
⁶⁴ Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
⁶⁵ NIHR Respiratory Biomedical Research Unit, University Hospital Southampton, Southampton, UK.
⁶⁶ The David Hide Asthma and Allergy Research Centre, Isle of Wight, UK.
⁶⁷ Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA.
⁶⁸ Novo Nordisk Foundation Center for Basic Metabolic Research, Section on Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁶⁹ Department of Clinical Epidemiology, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark.
⁷⁰ Department of Paediatric Pulmonology and Paediatric Allergy, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, GRIAC Research Institute, Groningen, the Netherlands.
⁷¹ School of Women's and Infants' Health, The University of Western Australia, Crawley, WA 6009, Australia.

PMID: 29016858
PMCID: PMC5656174
DOI: 10.1093/hmg/ddx290

Meta-Analysis

Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium

Gemma C Sharp et al. Hum Mol Genet. 2017.

. 2017 Oct 15;26(20):4067-4085.

doi: 10.1093/hmg/ddx290.

Authors

Affiliations

¹ MRC Integrative Epidemiology Unit.
² School of Social and Community Medicine.
³ School of Oral and Dental Sciences, University of Bristol, Bristol, UK.
⁴ ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
⁵ Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
⁶ Universitat Pompeu Fabra (UPF), Barcelona, Spain.
⁷ The Generation R Study Group.
⁸ Department of Epidemiology.
⁹ Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹⁰ Centre de Recherche du Centre Hospitalier, Université de Sherbrooke, QC, Canada.
¹¹ Center for Environmental Research and Children's Health (CERCH), School of Public Health, University of California Berkeley.
¹² Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
¹³ Department of Infection Epidemiology and Modeling, Norwegian Institute of Public Health, Oslo, Norway.
¹⁴ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA.
¹⁵ Telethon Kids Institute, University of Western Australia, Crawley, WA 6009, Australia.
¹⁶ National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA.
¹⁷ Department of Pulmonology, GRIAC Research Institute.
¹⁸ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹⁹ Epidemiology of Allergic and Respiratory Diseases Department (EPAR), Sorbonne Université, UPMC Univ Paris 06, INSERM, Pierre Louis Institute of Epidemiology and Public Health, Saint-Antoine Medical School, Paris, France.
²⁰ Department of Biological Sciences.
²¹ Center for Human Health and the Environment, North Carolina State University, NC, USA.
²² Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA.
²³ University of California San Francisco, CA, USA.
²⁴ HDF Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
²⁵ Computational Biology Core.
²⁶ Human Development & Health, Faculty of Medicine, University of Southampton, UK.
²⁷ Epigenetics Group, International Agency for Research on Cancer, Lyon, France.
²⁸ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
²⁹ Department of Epidemiology, School of Public Health, University of Michigan, MI, USA.
³⁰ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
³¹ Division of Epidemiology, Biostatistics, and Environmental Health Sciences, School of Public Health, University of Memphis, Memphis, TN, USA.
³² Department of Non-Communicable Disease, Norwegian Institute of Public Health, Oslo, Norway.
³³ Department of Global Public Health and Primary Care, University of Bergen, Norway.
³⁴ Medical Birth Registry of Norway, Norwegian Institute of Public Health, Bergen, Norway.
³⁵ The Curtin UWA Centre for Genetic Origins of Health and Disease, Faculty of Health Sciences, Curtin University Health Sciences, Curtin University and Faculty of Medicine Dentistry & Health Sciences, The University of Western Australia, Perth, Australia.
³⁶ Faculty of Medicine Dentistry & Health Sciences, The University of Western Australia, Perth, Australia.
³⁷ Department of Epidemiology, University of Groningen, University Medical Center Groningen, GRIAC Research Institute Groningen, The Netherlands.
³⁸ Research Unit for Gynaecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
³⁹ Department of Biological & Biomedical Sciences, North Carolina Central University, Durham, NC, USA.
⁴⁰ Obesity Prevention Program, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, USA.
⁴¹ CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.
⁴² Department of Epidemiology and Biostatistics, University of California San Francisco, CA, USA.
⁴³ School of Public Health, University of California Berkeley, CA, USA.
⁴⁴ Division of Research, Kaiser Permanente Northern California, CA, UDA.
⁴⁵ Department of Medicine, Université de Sherbrooke, QC, Canada.
⁴⁶ Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
⁴⁷ Children's Environmental Health & Disease Prevention Research Center at Dartmouth, Hanover, NH, USA.
⁴⁸ Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
⁴⁹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands.
⁵⁰ Epidemiology and Biostatistics Department, University of South Carolina (Columbia), SC, USA.
⁵¹ Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
⁵² Domain of Mental and Physical Health, Norwegian Institute of Public Health, Oslo, Norway.
⁵³ Center for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.
⁵⁴ Department of Public Health, School of Medicine, University of California, Davis, CA, USA.
⁵⁵ AJ Drexel Autism Institute, Drexel University, Philadelphia, PA, USA.
⁵⁶ Department of Biochemistry, Université de Sherbrooke, QC, Canada.
⁵⁷ ECOGENE-21 and Lipid Clinic, Chicoutimi Hospital, Saguenay, QC, Canada.
⁵⁸ Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA.
⁵⁹ Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
⁶⁰ Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
⁶¹ Sachs' Children's Hospital, South General Hospital, Stockholm, Sweden.
⁶² Department of Pediatric and Adolescent Medicine, Oslo University Hospital, Norway.
⁶³ Norwegian Institute of Public Health, Oslo Norway.
⁶⁴ Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
⁶⁵ NIHR Respiratory Biomedical Research Unit, University Hospital Southampton, Southampton, UK.
⁶⁶ The David Hide Asthma and Allergy Research Centre, Isle of Wight, UK.
⁶⁷ Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA.
⁶⁸ Novo Nordisk Foundation Center for Basic Metabolic Research, Section on Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁶⁹ Department of Clinical Epidemiology, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark.
⁷⁰ Department of Paediatric Pulmonology and Paediatric Allergy, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, GRIAC Research Institute, Groningen, the Netherlands.
⁷¹ School of Women's and Infants' Health, The University of Western Australia, Crawley, WA 6009, Australia.

PMID: 29016858
PMCID: PMC5656174
DOI: 10.1093/hmg/ddx290

Abstract

Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1 kg/m2), P < 1.06 × 10-7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for acausal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites. In conclusion, this well-powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large-scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.

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Figures

**Figure 1**
An overview of the study design.

**Figure 2**
A Manhattan plot for the meta-analysis of associations between maternal pre-pregnancy BMI and offspring DNA methylation at birth after adjustment for maternal covariates and estimated cell counts. The red line shows the Bonferroni threshold for multiple testing. Methylation sites that surpassed the Bonferroni-correction threshold (*P <* 1.06 × 10⁻⁷) before and after adjustment for estimated cell counts are highlighted in blue.

**Figure 3**
Volcano plots to illustrate the large increase in P-values after adjusting for estimated cell counts. Methylation sites that reached the Bonferroni threshold for multiple testing (1.06 × 10⁻⁷) are highlighted in blue.

**Figure 4**
Comparison of estimates of the effect of maternal BMI on offspring DNA methylation at birth and at adolescence. Of the 86 sites where maternal BMI at the start of pregnancy was associated with newborn blood methylation, 72 had the same direction of association in the analysis of adolescents. Plotted here are the 22/86 methylation sites with a P-value < 0.05 in the analysis of adolescents, ordered by effect size in newborns.

**Figure 5**
Comparison of estimates of the effect of maternal and paternal BMI on newborn DNA methylation. Of the 86 sites where maternal BMI at the start of pregnancy was associated with newborn blood methylation, we found 20 sites (plotted here) where the estimated effect of maternal BMI, adjusted for paternal BMI, had a P-value < 0.05 and was in the same direction and greater than the estimated effect of paternal BMI, adjusted for maternal BMI. Sites are ordered by P-value in the full maternal BMI meta-analysis.

See this image and copyright information in PMC

References

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Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium

Affiliations

Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical