title: Maternal plasma folate impacts differential DNA methylation in an epigenome-wide meta-analysis of newborns.
abstract: Folate is vital for fetal development. Periconceptional folic acid supplementation and food fortification are recommended to prevent neural tube defects. Mechanisms whereby periconceptional folate influences normal development and disease are poorly understood: epigenetics may be involved. We examine the association between maternal plasma folate during pregnancy and epigenome-wide DNA methylation using Illumina's HumanMethyl450 Beadchip in 1,988 newborns from two European cohorts. Here we report the combined covariate-adjusted results using meta-analysis and employ pathway and gene expression analyses. Four-hundred forty-three CpGs (320 genes) are significantly associated with maternal plasma folate levels during pregnancy (false discovery rate 5%); 48 are significant after Bonferroni correction. Most genes are not known for folate biology, including APC2, GRM8, SLC16A12, OPCML, PRPH, LHX1, KLK4 and PRSS21. Some relate to birth defects other than neural tube defects, neurological functions or varied aspects of embryonic development. These findings may inform how maternal folate impacts the developing epigenome and health outcomes in offspring.
authors: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA.
authors: Bonnie R
authors: http://orcid.org/0000-0001-7952-1180
authors: BR
authors: Joubert
authors: The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.|Department of Pediatrics, Division of Respiratory Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.|Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.
authors: Herman T
authors: HT
authors: den Dekker
authors: The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.|Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.|Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.
authors: Janine F
authors: JF
authors: Felix
authors: Norwegian Institute of Public Health, Oslo 0403, Norway.
authors: Jon
authors: J
authors: Bohlin
authors: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.
authors: Symen
authors: S
authors: Ligthart
authors: Department of Applied Sciences, School of Environmental and Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia.|Food and Nutrition Flagship, CSIRO, North Ryde, New South Wales 2113, Australia.
authors: Emma
authors: E
authors: Beckett
authors: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.|Department of Psychiatry, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.
authors: Henning
authors: http://orcid.org/0000-0002-4395-1397
authors: H
authors: Tiemeier
authors: Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.
authors: Joyce B
authors: JB
authors: van Meurs
authors: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.|Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.
authors: Andre G
authors: AG
authors: Uitterlinden
authors: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.
authors: Albert
authors: A
authors: Hofman
authors: Norwegian Institute of Public Health, Oslo 0403, Norway.
authors: Siri E
authors: SE
authors: Håberg
authors: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA.
authors: Sarah E
authors: SE
authors: Reese
authors: Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.
authors: Marjolein J
authors: MJ
authors: Peters
authors: Department of Clinical Molecular Biology, Institute of Clinical Medicine, University of Oslo, Oslo 0316, Norway.
authors: Bettina Kulle
authors: BK
authors: Andreassen
authors: Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.
authors: Eric A P
authors: EA
authors: Steegers
authors: Department of Research and Development, Centre for Clinical Research, Haukeland University Hospital, Bergen 5021, Norway.
authors: Roy M
authors: RM
authors: Nilsen
authors: Norwegian Institute of Public Health, Oslo 0403, Norway.|Department of Global Public Health and Primary Care, University of Bergen, Bergen 5018, Norway.
authors: Stein E
authors: SE
authors: Vollset
authors: Bevital A/S, Laboratoriebygget, Bergen 5018, Norway.
authors: Øivind
authors: Ø
authors: Midttun
authors: Department of Clinical Science, University of Bergen, Bergen 5018, Norway.|Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen 5018, Norway.
authors: Per M
authors: PM
authors: Ueland
authors: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.
authors: Oscar H
authors: OH
authors: Franco
authors: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.
authors: Abbas
authors: A
authors: Dehghan
authors: Department of Pediatrics, Division of Respiratory Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.
authors: Johan C
authors: JC
authors: de Jongste
authors: Public Health Sciences Program, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors: Michael C
authors: MC
authors: Wu
authors: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA.
authors: Tianyuan
authors: T
authors: Wang
authors: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA.
authors: Shyamal D
authors: SD
authors: Peddada
authors: The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.|Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.|Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.
authors: Vincent W V
authors: VW
authors: Jaddoe
authors: Norwegian Institute of Public Health, Oslo 0403, Norway.
authors: Wenche
authors: W
authors: Nystad
authors: The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.|Department of Pediatrics, Division of Respiratory Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.|Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, Netherlands.
authors: Liesbeth
authors: L
authors: Duijts
authors: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA.
authors: Stephanie J
authors: http://orcid.org/0000-0003-4911-5290
authors: SJ
authors: London
mesh_terms: D000328:Adult; D015815:Cell Adhesion Molecules / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005492:Folic Acid / Q000097:blood*; D058851:GPI-Linked Proteins / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007231:Infant, Newborn; D007610:Kallikreins / Q000235:genetics; D060850:LIM-Homeodomain Proteins / Q000235:genetics; D027501:Monocarboxylic Acid Transporters / Q000235:genetics; D064531:Peripherins / Q000235:genetics; D011247:Pregnancy; D012697:Serine Endopeptidases / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: C115681:APC2 protein, human; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D058851:GPI-Linked Proteins; C085473:LHX1 protein, human; D060850:LIM-Homeodomain Proteins; D027501:Monocarboxylic Acid Transporters; C059785:OPCML protein, human; C578994:PRPH protein, human; D064531:Peripherins; C527548:SLC16A12 protein, human; D014157:Transcription Factors; D005492:Folic Acid; D007610:Kallikreins; C120203:PRSS21 protein, human; D012697:Serine Endopeptidases; C120801:kallikrein 4