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

Edwina Yeung¹, Richard J Biedrzycki², Laura C Gómez Herrera^{3

4

5}, Prachand Issarapu⁶, John Dou⁷, Irene Fontes Marques^{8

9}, Sohail Rafik Mansuri¹⁰, Christian Magnus Page¹¹, Justin Harbs¹², Dennis Khodasevich¹³, Eric Poisel¹⁴, Zhongzheng Niu¹⁵, Catherine Allard¹⁶, Emma Casey¹⁷, Fernanda Morales Berstein^{18

19}, Giulia Mancano^{18

19}, Hannah R Elliott^{18

19}, Rebecca Richmond^{18

19}, Yiyan He²⁰, Justiina Ronkainen²⁰, Sylvain Sebert²⁰, Erin M Bell²¹, Gemma Sharp²², Sunni L Mumford²³, Enrique F Schisterman²³, Giriraj R Chandak¹⁰, Caroline H D Fall²⁴, Sirazul A Sahariah²⁵, Matt J Silver⁶, Andrew M Prentice⁶, Luigi Bouchard^{26

27}, Magnus Domellof²⁸, Christina West²⁸, Nina Holland¹³, Andres Cardenas²⁹, Brenda Eskenazi¹³, Lea Zillich¹⁴, Stephanie H Witt¹⁴, Tabea Send³⁰, Carrie Breton¹⁵, Kelly M Bakulski⁷, M Daniele Fallin³¹, Rebecca J Schmidt³², Dan J Stein^{33

34

35}, Heather J Zar^{35

36}, Vincent W V Jaddoe^{8

9}, John Wright³⁷, Regina Grazuleviciene³⁸, Kristine Bjerve Gutzkow³⁹, Jordi Sunyer^{3

4

5

40}, Anke Huels^{17

41}, Martine Vrijheid^{3

4

5}, Sophia Harlid¹², Stephanie London⁴², Marie-France Hivert^{43

44}, Janine Felix^{8

9}, Mariona Bustamante^{3

4

5}, Weihua Guan⁴⁵

Affiliations

¹ Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA.
² Division of Intramural Research, Glotech Inc., Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
³ ISGlobal, Institute for Global Health, Barcelona, Spain.
⁴ Universitat Pompeu Fabra (UPF), Barcelona, Spain.
⁵ CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
⁶ MRC Unit the Gambia at the London School of Hygiene and Tropical Medicine (LSHTM), Banjul, The Gambia.
⁷ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.
⁸ Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁹ Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹⁰ Genomic Research on Complex Diseases (GRC-Group), CSIR-Centre for Cellular and Molecular Biology, Hyderabad, Telangana, India.
¹¹ Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway.
¹² Department of Diagnostics and Intervention, Oncology, Umeå University, Umeå, Sweden.
¹³ Environmental Health Sciences, Berkeley Public Health, CERCH, University of California, Berkeley, California, USA.
¹⁴ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
¹⁵ Department of Population and Public Health Science, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
¹⁶ Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, Quebec, Canada.
¹⁷ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
¹⁸ Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
¹⁹ Bristol Medical School Population Health Sciences, University of Bristol, Bristol, UK.
²⁰ Research Unit of Population Health, University of Oulu, Oulu, Finland.
²¹ Department of Environmental Health Sciences and Epidemiology and Biostatistics, University at Albany School of Public Health, Albany, New York, USA.
²² Department of Psychology, University of Exeter, Exeter, UK.
²³ Department of Biostatistics, Epidemiology and Informatics and Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²⁴ MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK, UK.
²⁵ Centre for the Study of Social Change, Mumbai, India.
²⁶ Department of Biochemistry and Functional Genomics, Centre intégré Universitaire de santé et de Services Sociaux (CIUSSS) du Saguenay-Lac-St-Jean, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
²⁷ Department of Laboratory Medicine, CIUSSS du Saguenay-Lac-Saint-Jean - Hôpital de Chicoutimi, Chicoutimi, Quebec, Canada.
²⁸ Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden.
²⁹ Department of Epidemiology and Population Health, Stanford University, Stanford, California, USA.
³⁰ Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
³¹ Dean's Office, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
³² Department of Public Health Sciences and the M.I.N.D. Institute, School of Medicine, University of California, Davis, California, USA.
³³ Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
³⁴ Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
³⁵ South African Medical Research Council (SAMRC) Unit on Risk and Resilience in Mental Disorders, University of Cape Town, Cape Town, South Africa.
³⁶ Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Cape Town, South Africa.
³⁷ Bradford Institute for Health Research, Temple Bank House, Bradford Royal Infirmary, Bradford, UK.
³⁸ Department of Environmental Sciences, Vytautas Magnus University, Kaunas, Lithuania.
³⁹ Division of Climate and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway.
⁴⁰ IMIM-Parc Salut Mar, Barcelona, Spain.
⁴¹ Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
⁴² Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, North Carolina, USA.
⁴³ Division of Chronic Disease Research across the Lifecourse (CoRAL); Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, Massachusetts, USA.
⁴⁴ Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁴⁵ Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.

PMID: 38808605
PMCID: PMC11320347
DOI: 10.1111/acel.14194

Meta-Analysis

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

Edwina Yeung et al. Aging Cell. 2024 Aug.

. 2024 Aug;23(8):e14194.

doi: 10.1111/acel.14194. Epub 2024 May 29.

Authors

Affiliations

¹ Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA.
² Division of Intramural Research, Glotech Inc., Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
³ ISGlobal, Institute for Global Health, Barcelona, Spain.
⁴ Universitat Pompeu Fabra (UPF), Barcelona, Spain.
⁵ CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
⁶ MRC Unit the Gambia at the London School of Hygiene and Tropical Medicine (LSHTM), Banjul, The Gambia.
⁷ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.
⁸ Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁹ Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹⁰ Genomic Research on Complex Diseases (GRC-Group), CSIR-Centre for Cellular and Molecular Biology, Hyderabad, Telangana, India.
¹¹ Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway.
¹² Department of Diagnostics and Intervention, Oncology, Umeå University, Umeå, Sweden.
¹³ Environmental Health Sciences, Berkeley Public Health, CERCH, University of California, Berkeley, California, USA.
¹⁴ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
¹⁵ Department of Population and Public Health Science, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
¹⁶ Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, Quebec, Canada.
¹⁷ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
¹⁸ Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
¹⁹ Bristol Medical School Population Health Sciences, University of Bristol, Bristol, UK.
²⁰ Research Unit of Population Health, University of Oulu, Oulu, Finland.
²¹ Department of Environmental Health Sciences and Epidemiology and Biostatistics, University at Albany School of Public Health, Albany, New York, USA.
²² Department of Psychology, University of Exeter, Exeter, UK.
²³ Department of Biostatistics, Epidemiology and Informatics and Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²⁴ MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK, UK.
²⁵ Centre for the Study of Social Change, Mumbai, India.
²⁶ Department of Biochemistry and Functional Genomics, Centre intégré Universitaire de santé et de Services Sociaux (CIUSSS) du Saguenay-Lac-St-Jean, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
²⁷ Department of Laboratory Medicine, CIUSSS du Saguenay-Lac-Saint-Jean - Hôpital de Chicoutimi, Chicoutimi, Quebec, Canada.
²⁸ Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden.
²⁹ Department of Epidemiology and Population Health, Stanford University, Stanford, California, USA.
³⁰ Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
³¹ Dean's Office, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
³² Department of Public Health Sciences and the M.I.N.D. Institute, School of Medicine, University of California, Davis, California, USA.
³³ Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
³⁴ Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
³⁵ South African Medical Research Council (SAMRC) Unit on Risk and Resilience in Mental Disorders, University of Cape Town, Cape Town, South Africa.
³⁶ Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Cape Town, South Africa.
³⁷ Bradford Institute for Health Research, Temple Bank House, Bradford Royal Infirmary, Bradford, UK.
³⁸ Department of Environmental Sciences, Vytautas Magnus University, Kaunas, Lithuania.
³⁹ Division of Climate and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway.
⁴⁰ IMIM-Parc Salut Mar, Barcelona, Spain.
⁴¹ Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
⁴² Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, North Carolina, USA.
⁴³ Division of Chronic Disease Research across the Lifecourse (CoRAL); Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, Massachusetts, USA.
⁴⁴ Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁴⁵ Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.

PMID: 38808605
PMCID: PMC11320347
DOI: 10.1111/acel.14194

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.

Keywords: DNA methylation; aging; child; melatonin; receptor.

© 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.

PubMed Disclaimer

Conflict of interest statement

None to declare.

Figures

**FIGURE 1**
Manhattan plots for maternal age newborn blood EWAS. The Manhattan plots correspond to covariate adjustments for (a) cell type and batch, (b) additionally for maternal smoking, maternal education, maternal race/ethnicity/ancestry, parity, and selection (as applicable), and (c) additionally for BMI. Color indicates P_FDR < 0.05.

See this image and copyright information in PMC

References

1. Adkins, R. M. , Thomas, F. , Tylavsky, F. A. , & Krushkal, J. (2011). Parental ages and levels of DNA methylation in the newborn are correlated. BMC Medical Genetics, 12, 47. 10.1186/1471-2350-12-47 - DOI - PMC - PubMed
1. Ashapkin, V. , Suvorov, A. , Pilsner, J. R. , Krawetz, S. A. , & Sergeyev, O. (2023). Age‐associated epigenetic changes in mammalian sperm: Implications for offspring health and development. Human Reproduction Update, 29(1), 24–44. 10.1093/humupd/dmac033 - DOI - PMC - PubMed
1. Bakulski, K. M. , Feinberg, J. I. , Andrews, S. V. , Yang, J. , Brown, S. , McKenney, S. , Witter, F. , Walston, J. , Feinberg, A. P. , & Fallin, M. D. (2016). DNA methylation of cord blood cell types: Applications for mixed cell birth studies. Epigenetics, 11(5), 354–362. 10.1080/15592294.2016.1161875 - DOI - PMC - PubMed
1. Battram, T. , Yousefi, P. , Crawford, G. , Prince, C. , Sheikhali Babaei, M. , Sharp, G. , Hatcher, C. , Vega‐Salas, M. J. , Khodabakhsh, S. , Whitehurst, O. , Langdon, R. , Mahoney, L. , Elliott, H. R. , Mancano, G. , Lee, M. A. , Watkins, S. H. , Lay, A. C. , Hemani, G. , Gaunt, T. R. , … Suderman, M. (2022). The EWAS catalog: A database of epigenome‐wide association studies. Wellcome Open Res, 7, 41. 10.12688/wellcomeopenres.17598.2 - DOI - PMC - PubMed
1. Benjamini, Y. , & Hochberg, Y. (1995). Controlling the false discovery rate – a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society, Series B: Statistical Methodology, 57(1), 289–300. 10.1111/j.2517-6161.1995.tb02031.x - DOI

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources