title: An epigenome-wide association meta-analysis of prenatal maternal stress in neonates: A model approach for replication.
abstract: Prenatal maternal stress exposure has been associated with neonatal differential DNA methylation. However, the available evidence in humans is largely based on candidate gene methylation studies, where only a few CpG sites were evaluated. The aim of this study was to examine the association between prenatal exposure to maternal stress and offspring genome-wide cord blood methylation using different methods. First, we conducted a meta-analysis and follow-up pathway analyses. Second, we used novel region discovery methods [i.e., differentially methylated regions (DMRs) analyses]. To this end, we used data from two independent population-based studies, the Generation R Study (n = 912) and the Avon Longitudinal Study of Parents and Children (ALSPAC, n = 828), to (i) measure genome-wide DNA methylation in cord blood and (ii) extract a prenatal maternal stress composite. The meta-analysis (ntotal = 1,740) revealed no epigenome-wide (meta P <1.00e-07) associations of prenatal maternal stress exposure with neonatal differential DNA methylation. Follow-up analyses of the top hits derived from our epigenome-wide meta-analysis (meta P <1.00e-04) indicated an over-representation of the methyltransferase activity pathway. We identified no Bonferroni-corrected (P <1.00e-06) DMRs associated with prenatal maternal stress exposure. Combining data from two independent population-based samples in an epigenome-wide meta-analysis, the current study indicates that there are no large effects of prenatal maternal stress exposure on neonatal DNA methylation. Such replication efforts are essential in the search for robust associations, whether derived from candidate gene methylation or epigenome-wide studies.
authors.affiliation: a Centre for Child and Family Studies, Leiden University , Leiden , the Netherlands.|b Generation R Study Group, Erasmus MC-University Medical Center Rotterdam , Rotterdam , the Netherlands.|c Department of Child and Adolescent Psychiatry/ Psychology , Erasmus MC-University Medical Center Rotterdam , Rotterdam , the Netherlands.
authors.forename: Jolien
authors.initials: J
authors.lastname: Rijlaarsdam
authors.affiliation: b Generation R Study Group, Erasmus MC-University Medical Center Rotterdam , Rotterdam , the Netherlands.|d School of Pedagogical and Educational Sciences, Erasmus University Rotterdam , Rotterdam , the Netherlands.
authors.forename: Irene
authors.initials: I
authors.lastname: Pappa
authors.affiliation: e Institute of Psychiatry, Psychology and Neuroscience, King's College London , London , UK.
authors.forename: Esther
authors.initials: E
authors.lastname: Walton
authors.affiliation: a Centre for Child and Family Studies, Leiden University , Leiden , the Netherlands.
authors.forename: Marian J
authors.initials: MJ
authors.lastname: Bakermans-Kranenburg
authors.affiliation: a Centre for Child and Family Studies, Leiden University , Leiden , the Netherlands.|b Generation R Study Group, Erasmus MC-University Medical Center Rotterdam , Rotterdam , the Netherlands.
authors.forename: Viara R
authors.initials: VR
authors.lastname: Mileva-Seitz
authors.affiliation: a Centre for Child and Family Studies, Leiden University , Leiden , the Netherlands.
authors.forename: Ralph C A
authors.initials: RC
authors.lastname: Rippe
authors.affiliation: c Department of Child and Adolescent Psychiatry/ Psychology , Erasmus MC-University Medical Center Rotterdam , Rotterdam , the Netherlands.|f Department of Psychiatry , Erasmus MC-University Medical Center Rotterdam , Rotterdam , the Netherlands.
authors.forename: Sabine J
authors.initials: SJ
authors.lastname: Roza
authors.affiliation: b Generation R Study Group, Erasmus MC-University Medical Center Rotterdam , Rotterdam , the Netherlands.|g Department of Epidemiology , Erasmus MC-University Medical Center Rotterdam , Rotterdam , the Netherlands.|h Department of Pediatrics , Erasmus MC-University Medical Center Rotterdam , Rotterdam , the Netherlands.
authors.forename: Vincent W V
authors.initials: VW
authors.lastname: Jaddoe
authors.affiliation: c Department of Child and Adolescent Psychiatry/ Psychology , Erasmus MC-University Medical Center Rotterdam , Rotterdam , the Netherlands.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Verhulst
authors.affiliation: g Department of Epidemiology , Erasmus MC-University Medical Center Rotterdam , Rotterdam , the Netherlands.
authors.forename: Janine F
authors.initials: JF
authors.lastname: Felix
authors.affiliation: e Institute of Psychiatry, Psychology and Neuroscience, King's College London , London , UK.
authors.forename: Charlotte A M
authors.initials: CA
authors.lastname: Cecil
authors.affiliation: i Medical Research Council Integrative Epidemiology Unit, University of Bristol , Bristol , UK.
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Relton
authors.affiliation: i Medical Research Council Integrative Epidemiology Unit, University of Bristol , Bristol , UK.
authors.forename: Tom R
authors.initials: TR
authors.lastname: Gaunt
authors.affiliation: j School of Social and Community Medicine, University of Bristol , Bristol , UK.
authors.forename: Wendy
authors.initials: W
authors.lastname: McArdle
authors.affiliation: k University of Exeter Medical School, University of Exeter , Exeter , UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mill
authors.affiliation: e Institute of Psychiatry, Psychology and Neuroscience, King's College London , London , UK.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Barker
authors.affiliation: c Department of Child and Adolescent Psychiatry/ Psychology , Erasmus MC-University Medical Center Rotterdam , Rotterdam , the Netherlands.|f Department of Psychiatry , Erasmus MC-University Medical Center Rotterdam , Rotterdam , the Netherlands.|g Department of Epidemiology , Erasmus MC-University Medical Center Rotterdam , Rotterdam , the Netherlands.
authors.forename: Henning
authors.initials: H
authors.lastname: Tiemeier
authors.affiliation: a Centre for Child and Family Studies, Leiden University , Leiden , the Netherlands.|d School of Pedagogical and Educational Sciences, Erasmus University Rotterdam , Rotterdam , the Netherlands.
authors.forename: Marinus H
authors.initials: MH
authors.lastname: van IJzendoorn
mesh_terms: D000328:Adult; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D055106:Genome-Wide Association Study; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D018811:Maternal Exposure; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics*; D013315:Stress, Psychological / Q000235:genetics*
keywords: Birth cohort; DNA methylation; cord blood; epigenome-wide association study (EWAS); prenatal maternal stress