A Pregnancy and Childhood Epigenetics Consortium (PACE) meta-analysis highlights potential relationships between birth order and neonatal blood DNA methylation

Shaobo Li; Natalia Spitz; Akram Ghantous; Sarina Abrishamcar; Brigitte Reimann; Irene Marques; Matt J Silver; Sofía Aguilar-Lacasaña; Negusse Kitaba; Faisal I Rezwan; Stefan Röder; Lea Sirignano; Johanna Tuhkanen; Giulia Mancano; Gemma C Sharp; Catherine Metayer; Libby Morimoto; Dan J Stein; Heather J Zar; Rossella Alfano; Tim Nawrot; Congrong Wang; Eero Kajantie; Elina Keikkala; Sanna Mustaniemi; Justiina Ronkainen; Sylvain Sebert; Wnurinham Silva; Marja Vääräsmäki; Vincent W V Jaddoe; Robin M Bernstein; Andrew M Prentice; Marta Cosin-Tomas; Terence Dwyer; Siri Eldevik Håberg; Zdenko Herceg; Maria C Magnus; Monica Cheng Munthe-Kaas; Christian M Page; Maja Völker; Maria Gilles; Tabea Send; Stephanie Witt; Lea Zillich; Luigi Gagliardi; Lorenzo Richiardi; Darina Czamara; Katri Räikkönen; Lida Chatzi; Marina Vafeiadi; S Hasan Arshad; Susan Ewart; Michelle Plusquin; Janine F Felix; Sophie E Moore; Martine Vrijheid; John W Holloway; Wilfried Karmaus; Gunda Herberth; Ana Zenclussen; Fabian Streit; Jari Lahti; Anke Hüls; Thanh T Hoang; Stephanie J London; Joseph L Wiemels

doi:10.1038/s42003-023-05698-x

A Pregnancy and Childhood Epigenetics Consortium (PACE) meta-analysis highlights potential relationships between birth order and neonatal blood DNA methylation

Commun Biol. 2024 Jan 9;7(1):66. doi: 10.1038/s42003-023-05698-x.

Authors

Shaobo Li¹, Natalia Spitz², Akram Ghantous², Sarina Abrishamcar³, Brigitte Reimann⁴, Irene Marques^{5

6}, Matt J Silver⁷, Sofía Aguilar-Lacasaña^{8

9

10}, Negusse Kitaba¹¹, Faisal I Rezwan^{11

12}, Stefan Röder¹³, Lea Sirignano¹⁴, Johanna Tuhkanen¹⁵, Giulia Mancano¹⁶, Gemma C Sharp^{16

17}, Catherine Metayer¹⁸, Libby Morimoto¹⁸, Dan J Stein¹⁹, Heather J Zar^{19

20}, Rossella Alfano⁴, Tim Nawrot⁴, Congrong Wang⁴, Eero Kajantie^{21

22

23}, Elina Keikkala^{21

24}, Sanna Mustaniemi^{21

24}, Justiina Ronkainen²⁵, Sylvain Sebert²⁵, Wnurinham Silva²⁵, Marja Vääräsmäki^{21

24}, Vincent W V Jaddoe^{5

6}, Robin M Bernstein²⁶, Andrew M Prentice²⁷, Marta Cosin-Tomas^{8

9

10}, Terence Dwyer²⁸, Siri Eldevik Håberg²⁹, Zdenko Herceg², Maria C Magnus²⁹, Monica Cheng Munthe-Kaas³⁰, Christian M Page^{29

31}, Maja Völker¹⁴, Maria Gilles³², Tabea Send³², Stephanie Witt¹⁴, Lea Zillich¹⁴, Luigi Gagliardi³³, Lorenzo Richiardi³⁴, Darina Czamara¹⁵, Katri Räikkönen¹⁵, Lida Chatzi³⁵, Marina Vafeiadi³⁶, S Hasan Arshad^{37

38}, Susan Ewart³⁹, Michelle Plusquin⁴, Janine F Felix^{5

6}, Sophie E Moore⁴⁰, Martine Vrijheid^{8

10}, John W Holloway^{11

37}, Wilfried Karmaus⁴¹, Gunda Herberth¹³, Ana Zenclussen^{13

42}, Fabian Streit¹⁴, Jari Lahti¹⁵, Anke Hüls^{3

43}, Thanh T Hoang⁴⁴, Stephanie J London⁴⁴, Joseph L Wiemels⁴⁵

Affiliations

¹ Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, California, USA.
² Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, Lyon, France.
³ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
⁴ Centre for Environmental Sciences, UHasselt, Agoralaan, Building D, 3590, Diepenbeek, Belgium.
⁵ The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
⁶ Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
⁷ Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, London, UK.
⁸ ISGlobal, Institute for Global Health, Barcelona, Spain.
⁹ Universitat Pompeu Fabra (UPF), Barcelona, Spain.
¹⁰ CIBER Epidemiología y Salud Pública, Madrid, Spain.
¹¹ Human Development and Health, Faculty of Medicine, Southampton General Hospital, University of Southampton, Southampton, UK.
¹² Department of Computer Science, Aberystwyth University, Aberystwyth, Ceredigion, SY23 3DB, UK.
¹³ Department of Environmental Immunology, Helmholtz Centre for Environmental Research -UFZ, Leipzig, Germany.
¹⁴ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
¹⁵ Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland.
¹⁶ MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
¹⁷ School of Psychology, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.
¹⁸ School of Public Health, University of California Berkeley, Berkeley, California, USA.
¹⁹ SAMRC Unit on Risk & Resilience in Mental Disorders, Dept of Psychiatry & Neuroscience Institute, University of Cape Town, Rondebosch, South Africa.
²⁰ Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Rondebosch, South Africa.
²¹ Clinical Medicine Research Unit, Medical Research Center Oulu, Oulu University, Hospital and University of Oulu, Oulu, Finland.
²² Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
²³ Pediatric Research Centre, Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
²⁴ Population Health Unit, Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Oulu, Finland.
²⁵ Research Unit of Population Health, Faculty of Medicine, University of Oulu, Oulu, Finland.
²⁶ Department of Anthropology and Institute of Behavioral Science, University of Colorado Boulder, Boulder, CO, USA.
²⁷ MRC Unit The Gambia at the London School of Hygiene & Tropical Medicine, Fajara, The Gambia.
²⁸ Nuffield Department of Women's & Reproductive Health, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
²⁹ Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
³⁰ Department of Pediatric Oncology and Hematology, Oslo University Hospital, Norwegian Institute of Public Health, Oslo, Norway.
³¹ Department of Physical Health and Aging, Division for Mental and Physical Health, Norwegian Institute of Public Health, Oslo, Norway.
³² Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
³³ Woman and Child Health Department, Ospedale Versilia, AUSL Toscana Nord Ovest, Pisa, Italy.
³⁴ Department of Medical Sciences, University of Turin, CPO Piemonte, Turin, Italy.
³⁵ Department of Population and Public Health Sciences, Keck School of Medicine of USC. University of Southern California, Los Angeles, CA, USA.
³⁶ Department of Social Medicine, Faculty of Medicine, University of Crete, Heraklion, Greece.
³⁷ Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
³⁸ David Hide Asthma and Allergy Research Centre, Isle of Wight, UK.
³⁹ College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA.
⁴⁰ Department of Women & Children's Health, King's College London, London, UK.
⁴¹ Division of Epidemiology, Biostatistics, and Environmental Health, University of Memphis, Memphis, TN, USA.
⁴² Perinatal Immunology, Medical Faculty, Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, Leipzig, Germany.
⁴³ Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
⁴⁴ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
⁴⁵ Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, California, USA. wiemels@usc.edu.

Abstract

Higher birth order is associated with altered risk of many disease states. Changes in placentation and exposures to in utero growth factors with successive pregnancies may impact later life disease risk via persistent DNA methylation alterations. We investigated birth order with Illumina DNA methylation array data in each of 16 birth cohorts (8164 newborns) with European, African, and Latino ancestries from the Pregnancy and Childhood Epigenetics Consortium. Meta-analyzed data demonstrated systematic DNA methylation variation in 341 CpGs (FDR adjusted P < 0.05) and 1107 regions. Forty CpGs were located within known quantitative trait loci for gene expression traits in blood, and trait enrichment analysis suggested a strong association with immune-related, transcriptional control, and blood pressure regulation phenotypes. Decreasing fertility rates worldwide with the concomitant increased proportion of first-born children highlights a potential reflection of birth order-related epigenomic states on changing disease incidence trends.

Publication types

Meta-Analysis
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Birth Order*
Child
DNA Methylation*
Epigenesis, Genetic
Epigenomics
Female
Humans
Infant, Newborn
Pregnancy

Abstract

Publication types

MeSH terms

Grants and funding