Determinants of maternal pregnancy one-carbon metabolism and newborn human DNA methylation profiles.
Maternal one-carbon (1-C) metabolism provides methylgroups for fetal development and programing by DNA methylation as one of the underlying epigenetic mechanisms. We aimed to investigate maternal 1-C biomarkers, folic acid supplement use, and MTHFR C677T genotype as determinants of 1-C metabolism in early pregnancy in association with newborn DNA methylation levels of fetal growth and neurodevelopment candidate genes. The participants were 463 mother-child pairs of Dutch national origin from a large population-based birth cohort in Rotterdam, The Netherlands. In early pregnancy (median 13.0 weeks, 90% range 10.4-17.1), we assessed the maternal folate and homocysteine blood concentrations, folic acid supplement use, and the MTHFR C677T genotype in mothers and newborns. In newborns, DNA methylation was measured in umbilical cord blood white blood cells at 11 regions of the seven genes: NR3C1, DRD4, 5-HTT, IGF2DMR, H19, KCNQ1OT1, and MTHFR. The associations between the 1-C determinants and DNA methylation were examined using linear mixed models. An association was observed between maternal folate deficiency and lower newborn DNA methylation, which attenuated after adjustment for potential confounders. The maternal MTHFR TT genotype was significantly associated with lower DNA methylation. However, maternal homocysteine and folate concentrations, folic acid supplement use, and the MTHFR genotype in the newborn were not associated with newborn DNA methylation. The maternal MTHFR C677T genotype, as a determinant of folate status and 1-C metabolism, is associated with variations in the epigenome of a selection of genes in newborns. Research on the implications of these variations in methylation on gene expression and health is recommended.
The Generation R Study GroupDepartment of Child and Adolescent PsychiatryDepartment of Obstetrics and GynecologyDepartment of Internal MedicineDepartment of EpidemiologyDepartment of PaediatricsDepartment of BiostatisticsDepartment of PsychiatryErasmus MC, University Medical Centre Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands The Generation R Study GroupDepartment of Child and Adolescent PsychiatryDepartment of Obstetrics and GynecologyDepartment of Internal MedicineDepartment of EpidemiologyDepartment of PaediatricsDepartment of BiostatisticsDepartment of PsychiatryErasmus MC, University Medical Centre Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands The Generation R Study GroupDepartment of Child and Adolescent PsychiatryDepartment of Obstetrics and GynecologyDepartment of Internal MedicineDepartment of EpidemiologyDepartment of PaediatricsDepartment of BiostatisticsDepartment of PsychiatryErasmus MC, University Medical Centre Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
Nina H
NH
van Mil
The Generation R Study GroupDepartment of Child and Adolescent PsychiatryDepartment of Obstetrics and GynecologyDepartment of Internal MedicineDepartment of EpidemiologyDepartment of PaediatricsDepartment of BiostatisticsDepartment of PsychiatryErasmus MC, University Medical Centre Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands The Generation R Study GroupDepartment of Child and Adolescent PsychiatryDepartment of Obstetrics and GynecologyDepartment of Internal MedicineDepartment of EpidemiologyDepartment of PaediatricsDepartment of BiostatisticsDepartment of PsychiatryErasmus MC, University Medical Centre Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
Marieke I
MI
Bouwland-Both
The Generation R Study GroupDepartment of Child and Adolescent PsychiatryDepartment of Obstetrics and GynecologyDepartment of Internal MedicineDepartment of EpidemiologyDepartment of PaediatricsDepartment of BiostatisticsDepartment of PsychiatryErasmus MC, University Medical Centre Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
Lisette
L
Stolk
The Generation R Study GroupDepartment of Child and Adolescent PsychiatryDepartment of Obstetrics and GynecologyDepartment of Internal MedicineDepartment of EpidemiologyDepartment of PaediatricsDepartment of BiostatisticsDepartment of PsychiatryErasmus MC, University Medical Centre Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
Michael M P J
MM
Verbiest
The Generation R Study GroupDepartment of Child and Adolescent PsychiatryDepartment of Obstetrics and GynecologyDepartment of Internal MedicineDepartment of EpidemiologyDepartment of PaediatricsDepartment of BiostatisticsDepartment of PsychiatryErasmus MC, University Medical Centre Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
Albert
A
Hofman
The Generation R Study GroupDepartment of Child and Adolescent PsychiatryDepartment of Obstetrics and GynecologyDepartment of Internal MedicineDepartment of EpidemiologyDepartment of PaediatricsDepartment of BiostatisticsDepartment of PsychiatryErasmus MC, University Medical Centre Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands The Generation R Study GroupDepartment of Child and Adolescent PsychiatryDepartment of Obstetrics and GynecologyDepartment of Internal MedicineDepartment of EpidemiologyDepartment of PaediatricsDepartment of BiostatisticsDepartment of PsychiatryErasmus MC, University Medical Centre Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands The Generation R Study GroupDepartment of Child and Adolescent PsychiatryDepartment of Obstetrics and GynecologyDepartment of Internal MedicineDepartment of EpidemiologyDepartment of PaediatricsDepartment of BiostatisticsDepartment of PsychiatryErasmus MC, University Medical Centre Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
Vincent W V
VW
Jaddoe
The Generation R Study GroupDepartment of Child and Adolescent PsychiatryDepartment of Obstetrics and GynecologyDepartment of Internal MedicineDepartment of EpidemiologyDepartment of PaediatricsDepartment of BiostatisticsDepartment of PsychiatryErasmus MC, University Medical Centre Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
Frank C
FC
Verhulst
The Generation R Study GroupDepartment of Child and Adolescent PsychiatryDepartment of Obstetrics and GynecologyDepartment of Internal MedicineDepartment of EpidemiologyDepartment of PaediatricsDepartment of BiostatisticsDepartment of PsychiatryErasmus MC, University Medical Centre Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
Paul H C
PH
Eilers
The Generation R Study GroupDepartment of Child and Adolescent PsychiatryDepartment of Obstetrics and GynecologyDepartment of Internal MedicineDepartment of EpidemiologyDepartment of PaediatricsDepartment of BiostatisticsDepartment of PsychiatryErasmus MC, University Medical Centre Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands The Generation R Study GroupDepartment of Child and Adolescent PsychiatryDepartment of Obstetrics and GynecologyDepartment of Internal MedicineDepartment of EpidemiologyDepartment of PaediatricsDepartment of BiostatisticsDepartment of PsychiatryErasmus MC, University Medical Centre Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
Andre G
AG
Uitterlinden
The Generation R Study GroupDepartment of Child and Adolescent PsychiatryDepartment of Obstetrics and GynecologyDepartment of Internal MedicineDepartment of EpidemiologyDepartment of PaediatricsDepartment of BiostatisticsDepartment of PsychiatryErasmus MC, University Medical Centre Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
Eric A P
EA
Steegers
The Generation R Study GroupDepartment of Child and Adolescent PsychiatryDepartment of Obstetrics and GynecologyDepartment of Internal MedicineDepartment of EpidemiologyDepartment of PaediatricsDepartment of BiostatisticsDepartment of PsychiatryErasmus MC, University Medical Centre Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands The Generation R Study GroupDepartment of Child and Adolescent PsychiatryDepartment of Obstetrics and GynecologyDepartment of Internal MedicineDepartment of EpidemiologyDepartment of PaediatricsDepartment of BiostatisticsDepartment of PsychiatryErasmus MC, University Medical Centre Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands The Generation R Study GroupDepartment of Child and Adolescent PsychiatryDepartment of Obstetrics and GynecologyDepartment of Internal MedicineDepartment of EpidemiologyDepartment of PaediatricsDepartment of BiostatisticsDepartment of PsychiatryErasmus MC, University Medical Centre Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
Henning
H
Tiemeier
The Generation R Study GroupDepartment of Child and Adolescent PsychiatryDepartment of Obstetrics and GynecologyDepartment of Internal MedicineDepartment of EpidemiologyDepartment of PaediatricsDepartment of BiostatisticsDepartment of PsychiatryErasmus MC, University Medical Centre Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands r.steegers@erasmusmc.nl.
Régine P M
RP
Steegers-Theunissen
D000328:Adult; D002244:Carbon / Q000378:metabolism*; D015331:Cohort Studies; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation / Q000502:physiology*; D044127:Epigenesis, Genetic / Q000502:physiology; D005260:Female; D047109:Fetal Development / Q000502:physiology; D005492:Folic Acid / Q000097:blood / Q000378:metabolism; D005838:Genotype; D006710:Homocysteine / Q000097:blood; D006801:Humans; D007231:Infant, Newborn / Q000378:metabolism*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D011247:Pregnancy / Q000235:genetics* / Q000378:metabolism*
D006710:Homocysteine; D002244:Carbon; D004247:DNA; D005492:Folic Acid; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)