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Maternal age is related to offspring DNA methylation: a meta-analysis of results from the PACE consortium

Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of ol...

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Main Authors: Yeung, Edwina (Author) , Biedrzycki, Richard J. (Author) , Gómez Herrera, Laura C. (Author) , Issarapu, Prachand (Author) , Dou, John (Author) , Marques, Irene Fontes (Author) , Mansuri, Sohail Rafik (Author) , Page, Christian Magnus (Author) , Harbs, Justin (Author) , Khodasevich, Dennis (Author) , Zillich, Eric (Author) , Niu, Zhongzheng (Author) , Allard, Catherine (Author) , Casey, Emma (Author) , Berstein, Fernanda Morales (Author) , Mancano, Giulia (Author) , Elliott, Hannah R. (Author) , Richmond, Rebecca (Author) , He, Yiyan (Author) , Ronkainen, Justiina (Author) , Sebert, Sylvain (Author) , Bell, Erin M. (Author) , Sharp, Gemma (Author) , Mumford, Sunni L. (Author) , Schisterman, Enrique F. (Author) , Chandak, Giriraj R. (Author) , Fall, Caroline H. D. (Author) , Sahariah, Sirazul A. (Author) , Silver, Matt J. (Author) , Prentice, Andrew M. (Author) , Bouchard, Luigi (Author) , Domellof, Magnus (Author) , West, Christina (Author) , Holland, Nina (Author) , Cardenas, Andres (Author) , Eskenazi, Brenda (Author) , Zillich, Lea (Author) , Witt, Stephanie (Author) , Send, Tabea (Author) , Breton, Carrie (Author) , Bakulski, Kelly M. (Author) , Fallin, M. Daniele (Author) , Schmidt, Rebecca J. (Author) , Stein, Dan J. (Author) , Zar, Heather J. (Author) , Jaddoe, Vincent W. V. (Author) , Wright, John (Author) , Grazuleviciene, Regina (Author) , Gutzkow, Kristine Bjerve (Author) , Sunyer, Jordi (Author) , Huels, Anke (Author) , Vrijheid, Martine (Author) , Harlid, Sophia (Author) , London, Stephanie (Author) , Hivert, Marie-France (Author) , Felix, Janine (Author) , Bustamante, Mariona (Author) , Guan, Weihua (Author)
Format: Article (Journal)
Language:English
Published: August 2024
In: Aging cell
Year: 2024, Volume: 23, Issue: 8, Pages: 1-16
ISSN:1474-9726
DOI:10.1111/acel.14194
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1111/acel.14194
Verlag, kostenfrei, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1111/acel.14194
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Author Notes:Edwina Yeung, Richard J. Biedrzycki, Laura C. Gómez Herrera, Prachand Issarapu, John Dou, Irene Fontes Marques, Sohail Rafik Mansuri, Christian Magnus Page, Justin Harbs, Dennis Khodasevich, Eric Poisel, Zhongzheng Niu, Catherine Allard, Emma Casey, Fernanda Morales Berstein, Giulia Mancano, Hannah R. Elliott, Rebecca Richmond, Yiyan He, Justiina Ronkainen, Sylvain Sebert, Erin M. Bell, Gemma Sharp, Sunni L. Mumford, Enrique F. Schisterman, Giriraj R. Chandak, Caroline H. D. Fall, Sirazul A. Sahariah, Matt J. Silver, Andrew M. Prentice, Luigi Bouchard, Magnus Domellof, Christina West, Nina Holland, Andres Cardenas, Brenda Eskenazi, Lea Zillich, Stephanie H. Witt, Tabea Send, Carrie Breton, Kelly M. Bakulski, M. Daniele Fallin, Rebecca J. Schmidt, Dan J. Stein, Heather J. Zar, Vincent W. V. Jaddoe, John Wright, Regina Grazuleviciene, Kristine Bjerve Gutzkow, Jordi Sunyer, Anke Huels, Martine Vrijheid, Sophia Harlid, Stephanie London, Marie-France Hivert, Janine Felix, Mariona Bustamante, Weihua Guan

MARC

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520 |a Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta-analyzed epigenome-wide associations of parental age with offspring blood DNAm of over 9500 newborns and 2000 children (5-10 years old) from the Pregnancy and Childhood Epigenetics consortium. In newborns, we identified 33 CpG sites in 13 loci with DNAm associated with maternal age (PFDR < 0.05). Eight of these CpGs were located near/in the MTNR1B gene, coding for a melatonin receptor. Regional analysis identified them together as a differentially methylated region consisting of 9 CpGs in/near MTNR1B, at which higher DNAm was associated with greater maternal age (PFDR = 6.92 × 10−8) in newborns. In childhood blood samples, these differences in blood DNAm of MTNR1B CpGs were nominally significant (p < 0.05) and retained the same positive direction, suggesting persistence of associations. Maternal age was also positively associated with higher DNA methylation at three CpGs in R℡1-TNFRSF6B at birth (PFDR < 0.05) and nominally in childhood (p < 0.0001). Of the remaining 10 CpGs also persistent in childhood, methylation at cg26709300 in YPEL3/BOLA2B in external data was associated with expression of ITGAL, an immune regulator. While further study is needed to establish causality, particularly due to the small effect sizes observed, our results potentially support offspring DNAm as a mechanism underlying associations of maternal age with child health. 
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