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 AlfanoTim 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*

*Corresponding author for this work

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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.

Original languageEnglish
Article number66
JournalCommunications Biology
Volume7
Issue number1
DOIs
Publication statusPublished - 9 Jan 2024

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Publisher Copyright: © 2024, The Author(s).

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