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

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

doi:10.1111/acel.14194

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

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

Department of Epidemiology and Environmental Health

National Institutes of Health
(ISGlobal) Instituto de Salud Global de Barcelona
Pompeu Fabra University
Centro de Investigación Biomédicaen Red de Epidemiología y Salud Pública (CIBERESP)
London School of Hygiene and Tropical Medicine
University of Michigan, Ann Arbor
Erasmus University Rotterdam
CSIR - Centre for Cellular Molecular Biology
University of Oslo
Umeå University
University of California at Berkeley
Heidelberg University
Centre Hospitalier Universitaire de Sherbrooke
Emory University
University of Bristol
University of Oulu
SUNY Albany
University of Exeter
University of Pennsylvania
MRC Lifecourse Epidemiology Unit
Centre for the Study of Social Change
Université de Sherbrooke
Stanford University
University of Southern California
University of California at Davis
University of Cape Town
Bradford Teaching Hospitals NHS Foundation Trust
Vytautas Magnus University
Norwegian Institute of Public Health
Municipal Institute for Medical Research Hospital del Mar
Harvard Pilgrim Health Care Institute
Massachusetts General Hospital
University of Minnesota Twin Cities

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

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 (P_FDR < 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 (P_FDR = 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 RTEL1-TNFRSF6B at birth (P_FDR < 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.

Original language	English
Article number	e14194
Journal	Aging Cell
Volume	23
Issue number	8
DOIs	https://doi.org/10.1111/acel.14194
State	Published - Aug 2024

Keywords

DNA methylation
aging
child
melatonin
receptor

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10.1111/acel.14194

Cite this

Yeung, E., Biedrzycki, R. J., Gómez Herrera, L. C., Issarapu, P., Dou, J., Marques, I. F., Mansuri, S. R., Page, C. M., Harbs, J., Khodasevich, D., Poisel, E., Niu, Z., Allard, C., Casey, E., Berstein, F. M., Mancano, G., Elliott, H. R., Richmond, R., He, Y., ... Guan, W. (2024). Maternal age is related to offspring DNA methylation: A meta-analysis of results from the PACE consortium. Aging Cell, 23(8), Article e14194. https://doi.org/10.1111/acel.14194

@article{5e85fed35b904a9fad049c97ec6c4451,

title = "Maternal age is related to offspring DNA methylation: A meta-analysis of results from the PACE consortium",

abstract = "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 RTEL1-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.",

keywords = "DNA methylation, aging, child, melatonin, receptor",

author = "Edwina Yeung and Biedrzycki, \{Richard J.\} and G{\'o}mez Herrera, \{Laura C.\} and Prachand Issarapu and John Dou and Marques, \{Irene Fontes\} and Mansuri, \{Sohail Rafik\} and Page, \{Christian Magnus\} and Justin Harbs and Dennis Khodasevich and Eric Poisel and Zhongzheng Niu and Catherine Allard and Emma Casey and Berstein, \{Fernanda Morales\} and Giulia Mancano and Elliott, \{Hannah R.\} and Rebecca Richmond and Yiyan He and Justiina Ronkainen and Sylvain Sebert and Bell, \{Erin M.\} and Gemma Sharp and Mumford, \{Sunni L.\} and Schisterman, \{Enrique F.\} and Chandak, \{Giriraj R.\} and Fall, \{Caroline H.D.\} and Sahariah, \{Sirazul A.\} and Silver, \{Matt J.\} and Prentice, \{Andrew M.\} and Luigi Bouchard and Magnus Domellof and Christina West and Nina Holland and Andres Cardenas and Brenda Eskenazi and Lea Zillich and Witt, \{Stephanie H.\} and Tabea Send and Carrie Breton and Bakulski, \{Kelly M.\} and Fallin, \{M. Daniele\} and Schmidt, \{Rebecca J.\} and Stein, \{Dan J.\} and Zar, \{Heather J.\} and Jaddoe, \{Vincent W.V.\} and John Wright and Regina Grazuleviciene and Gutzkow, \{Kristine Bjerve\} and Jordi Sunyer and Anke Huels and Martine Vrijheid and Sophia Harlid and Stephanie London and Hivert, \{Marie France\} and Janine Felix and Mariona Bustamante and Weihua Guan",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley \& Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.",

year = "2024",

month = aug,

doi = "10.1111/acel.14194",

language = "English",

volume = "23",

journal = "Aging Cell",

issn = "1474-9718",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "8",

}

Yeung, E, Biedrzycki, RJ, Gómez Herrera, LC, Issarapu, P, Dou, J, Marques, IF, Mansuri, SR, Page, CM, Harbs, J, Khodasevich, D, Poisel, E, Niu, Z, Allard, C, Casey, E, Berstein, FM, Mancano, G, Elliott, HR, Richmond, R, He, Y, Ronkainen, J, Sebert, S, Bell, EM, Sharp, G, Mumford, SL, Schisterman, EF, Chandak, GR, Fall, CHD, Sahariah, SA, Silver, MJ, Prentice, AM, Bouchard, L, Domellof, M, West, C, Holland, N, Cardenas, A, Eskenazi, B, Zillich, L, Witt, SH, Send, T, Breton, C, Bakulski, KM, Fallin, MD, Schmidt, RJ, Stein, DJ, Zar, HJ, Jaddoe, VWV, Wright, J, Grazuleviciene, R, Gutzkow, KB, Sunyer, J, Huels, A, Vrijheid, M, Harlid, S, London, S, Hivert, MF, Felix, J, Bustamante, M & Guan, W 2024, 'Maternal age is related to offspring DNA methylation: A meta-analysis of results from the PACE consortium', Aging Cell, vol. 23, no. 8, e14194. https://doi.org/10.1111/acel.14194

TY - JOUR

T1 - Maternal age is related to offspring DNA methylation

T2 - A meta-analysis of results from the PACE consortium

AU - Yeung, Edwina

AU - Biedrzycki, Richard J.

AU - Gómez Herrera, Laura C.

AU - Issarapu, Prachand

AU - Dou, John

AU - Marques, Irene Fontes

AU - Mansuri, Sohail Rafik

AU - Page, Christian Magnus

AU - Harbs, Justin

AU - Khodasevich, Dennis

AU - Poisel, Eric

AU - Niu, Zhongzheng

AU - Allard, Catherine

AU - Casey, Emma

AU - Berstein, Fernanda Morales

AU - Mancano, Giulia

AU - Elliott, Hannah R.

AU - Richmond, Rebecca

AU - He, Yiyan

AU - Ronkainen, Justiina

AU - Sebert, Sylvain

AU - Bell, Erin M.

AU - Sharp, Gemma

AU - Mumford, Sunni L.

AU - Schisterman, Enrique F.

AU - Chandak, Giriraj R.

AU - Fall, Caroline H.D.

AU - Sahariah, Sirazul A.

AU - Silver, Matt J.

AU - Prentice, Andrew M.

AU - Bouchard, Luigi

AU - Domellof, Magnus

AU - West, Christina

AU - Holland, Nina

AU - Cardenas, Andres

AU - Eskenazi, Brenda

AU - Zillich, Lea

AU - Witt, Stephanie H.

AU - Send, Tabea

AU - Breton, Carrie

AU - Bakulski, Kelly M.

AU - Fallin, M. Daniele

AU - Schmidt, Rebecca J.

AU - Stein, Dan J.

AU - Zar, Heather J.

AU - Jaddoe, Vincent W.V.

AU - Wright, John

AU - Grazuleviciene, Regina

AU - Gutzkow, Kristine Bjerve

AU - Sunyer, Jordi

AU - Huels, Anke

AU - Vrijheid, Martine

AU - Harlid, Sophia

AU - London, Stephanie

AU - Hivert, Marie France

AU - Felix, Janine

AU - Bustamante, Mariona

AU - Guan, Weihua

N1 - Publisher Copyright: © 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

PY - 2024/8

Y1 - 2024/8

N2 - 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 RTEL1-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.

AB - 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 RTEL1-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.

KW - DNA methylation

KW - aging

KW - child

KW - melatonin

KW - receptor

UR - https://www.scopus.com/pages/publications/85194821046

U2 - 10.1111/acel.14194

DO - 10.1111/acel.14194

M3 - Article

C2 - 38808605

AN - SCOPUS:85194821046

SN - 1474-9718

VL - 23

JO - Aging Cell

JF - Aging Cell

IS - 8

M1 - e14194

ER -

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

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Keywords

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