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

Author:

Yeung Edwina1ORCID,Biedrzycki Richard J.2,Gómez Herrera Laura C.345,Issarapu Prachand6,Dou John7,Marques Irene Fontes89,Mansuri Sohail Rafik10,Page Christian Magnus11,Harbs Justin12,Khodasevich Dennis13,Poisel Eric14,Niu Zhongzheng15,Allard Catherine16,Casey Emma17,Berstein Fernanda Morales1819,Mancano Giulia1819,Elliott Hannah R.1819,Richmond Rebecca1819,He Yiyan20,Ronkainen Justiina20,Sebert Sylvain20,Bell Erin M.21,Sharp Gemma22,Mumford Sunni L.23,Schisterman Enrique F.23,Chandak Giriraj R.10,Fall Caroline H. D.24,Sahariah Sirazul A.25,Silver Matt J.6,Prentice Andrew M.6,Bouchard Luigi2627,Domellof Magnus28,West Christina28,Holland Nina13,Cardenas Andres29ORCID,Eskenazi Brenda13,Zillich Lea14,Witt Stephanie H.14,Send Tabea30,Breton Carrie15,Bakulski Kelly M.7,Fallin M. Daniele31,Schmidt Rebecca J.32,Stein Dan J.333435,Zar Heather J.3536,Jaddoe Vincent W. V.89,Wright John37,Grazuleviciene Regina38,Gutzkow Kristine Bjerve39,Sunyer Jordi34540,Huels Anke1741,Vrijheid Martine345,Harlid Sophia12,London Stephanie42,Hivert Marie‐France4344,Felix Janine89,Bustamante Mariona345,Guan Weihua45

Affiliation:

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

Abstract

AbstractWorldwide 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.

Funder

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Publisher

Wiley

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