Maternal age is related to offspring DNA methylation: A meta-analysis of results from the PACE consortium.
Journal: Aging cell
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Affiliated Institutions:
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.
Division of Intramural Research, Glotech Inc., Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
ISGlobal, Institute for Global Health, Barcelona, Spain.
MRC Unit the Gambia at the London School of Hygiene and Tropical Medicine (LSHTM), Banjul, The Gambia.
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.
Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Genomic Research on Complex Diseases (GRC-Group), CSIR-Centre for Cellular and Molecular Biology, Hyderabad, Telangana, India.
Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway.
Department of Diagnostics and Intervention, Oncology, Umeå University, Umeå, Sweden.
Environmental Health Sciences, Berkeley Public Health, CERCH, University of California, Berkeley, California, USA.
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Department of Population and Public Health Science, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, Quebec, Canada.
Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Research Unit of Population Health, University of Oulu, Oulu, Finland.
Department of Environmental Health Sciences and Epidemiology and Biostatistics, University at Albany School of Public Health, Albany, New York, USA.
Department of Psychology, University of Exeter, Exeter, UK.
Department of Biostatistics, Epidemiology and Informatics and Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK, UK.
Centre for the Study of Social Change, Mumbai, India.
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.
Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden.
Department of Epidemiology and Population Health, Stanford University, Stanford, California, USA.
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Dean's Office, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
Department of Public Health Sciences and the M.I.N.D. Institute, School of Medicine, University of California, Davis, California, USA.
Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
South African Medical Research Council (SAMRC) Unit on Risk and Resilience in Mental Disorders, University of Cape Town, Cape Town, South Africa.
Bradford Institute for Health Research, Temple Bank House, Bradford Royal Infirmary, Bradford, UK.
Department of Environmental Sciences, Vytautas Magnus University, Kaunas, Lithuania.
Division of Climate and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway.
Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, North Carolina, USA.
Division of Chronic Disease Research across the Lifecourse (CoRAL); Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, Massachusetts, USA.
Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
Abstract summary
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 < 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 = 6.92 × 10) 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 < 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.
Authors & Co-authors:
Yeung Edwina E
Biedrzycki Richard J RJ
Gómez Herrera Laura C LC
Issarapu Prachand P
Dou John J
Marques Irene Fontes IF
Mansuri Sohail Rafik SR
Page Christian Magnus CM
Harbs Justin J
Khodasevich Dennis D
Poisel Eric E
Niu Zhongzheng Z
Allard Catherine C
Casey Emma E
Berstein Fernanda Morales FM
Mancano Giulia G
Elliott Hannah R HR
Richmond Rebecca R
He Yiyan Y
Ronkainen Justiina J
Sebert Sylvain S
Bell Erin M EM
Sharp Gemma G
Mumford Sunni L SL
Schisterman Enrique F EF
Chandak Giriraj R GR
Fall Caroline H D CHD
Sahariah Sirazul A SA
Silver Matt J MJ
Prentice Andrew M AM
Bouchard Luigi L
Domellof Magnus M
West Christina C
Holland Nina N
Cardenas Andres A
Eskenazi Brenda B
Zillich Lea L
Witt Stephanie H SH
Send Tabea T
Breton Carrie C
Bakulski Kelly M KM
Fallin M Daniele MD
Schmidt Rebecca J RJ
Stein Dan J DJ
Zar Heather J HJ
Jaddoe Vincent W V VWV
Wright John J
Grazuleviciene Regina R
Gutzkow Kristine Bjerve KB
Sunyer Jordi J
Huels Anke A
Vrijheid Martine M
Harlid Sophia S
London Stephanie S
Hivert Marie-France MF
Felix Janine J
Bustamante Mariona M
Guan Weihua W
Study Outcome
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