title: Neonatal DNA methylation patterns associate with gestational age.
abstract: Risk for adverse neonatal outcome increases with declining gestational age (GA), and changes in DNA methylation may contribute to the relationship between GA and adverse health outcomes in offspring. To test this hypothesis, we evaluated the association between GA and more than 27,000 CpG sites in neonatal DNA extracted from umbilical cord blood from two prospectively-characterized cohorts: (1) a discovery cohort consisting of 259 neonates from women with a history of neuropsychiatric disorders and (2) a replication cohort consisting of 194 neonates of uncomplicated mothers. GA was determined by obstetrician report and maternal last menstrual period. The associations between proportion of DNA methylated and GA were evaluated by fitting a separate linear mixed effects model for each CpG site, adjusting for relevant covariates including neonatal sex, race, parity, birth weight percentile and chip effects. CpG sites in 39 genes were associated with GA (false discovery rate < 0.05) in the discovery cohort. The same CpG sites in 25 of these genes replicated in the replication cohort, with each association replicating in the same direction. Notably, these CpG sites were located in genes previously implicated in labor and delivery (e.g., AVP, OXT, CRHBP and ESR1) or that may influence the risk for adverse health outcomes later in life (e.g., DUOX2, TMEM176A and CASP8). All associations were independent of method of delivery or induction of labor. These results suggest neonatal DNA methylation varies with GA even in term deliveries. The potential contribution of these changes to clinically significant postnatal outcomes warrants further investigation.
authors.affiliation: Genetics and Molecular Biology Program, Emory University, Atlanta, GA, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Schroeder
authors.forename: Karen N
authors.initials: KN
authors.lastname: Conneely
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Cubells
authors.forename: Varun
authors.initials: V
authors.lastname: Kilaru
authors.forename: D Jeffrey
authors.initials: DJ
authors.lastname: Newport
authors.forename: Bettina T
authors.initials: BT
authors.lastname: Knight
authors.forename: Zachary N
authors.initials: ZN
authors.lastname: Stowe
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Brennan
authors.forename: Julia
authors.initials: J
authors.lastname: Krushkal
authors.forename: Frances A
authors.initials: FA
authors.lastname: Tylavsky
authors.forename: Robert N
authors.initials: RN
authors.lastname: Taylor
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Adkins
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Smith
mesh_terms: D001724:Birth Weight / Q000235:genetics; D015331:Cohort Studies; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D015894:Genome, Human; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy; D011256:Pregnancy Outcome