Neonatal DNA methylation patterns associate with gestational age

James Schroeder

Karen Conneely

Joseph Cubells

Varun Kilaru

Julia Krushkal+4 authors

Supplementary Material:

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^{Genetics and Molecular Biology Program; Emory University; Atlanta, GA USA;}

^{Department of Human Genetics, Emory University School of Medicine; Atlanta, GA USA;}

^{Psychiatry and Behavioral Sciences; Emory University School of Medicine; Atlanta, GA USA;}

^{Emory Women's Mental Health Program; Emory University School of Medicine; Atlanta, GA USA;}

^{Department of Gynecology and Obstetrics; Emory University School of Medicine; Atlanta, GA USA;}

^{Department of Psychology; Emory University; Atlanta, GA USA;}

^{Department of Preventive Medicine; University of Tennessee Health Science Center; Memphis, TN USA}

^{Department of Pediatrics; University of Tennessee Health Science Center; Memphis, TN USA}

^{Corresponding author.}

Correspondence to: Alicia K. Smith; Email: ude.yrome@3timska

Received 2011 Jul 27; Revised 2011 Sep 27; Accepted 2011 Oct 4.

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.

Key words: genome-wide DNA methylation, gestational age, arginine vasopressin and oxytocin

Abstract

Acknowledgments

The authors gratefully acknowledge the women who participated in this study, and the community obstetrical practices in the Atlanta and Memphis areas for assistance in sample collection. This study was supported, in part, by the Emory Biomarker Service Center.

Acknowledgments

Abbreviations

GA	gestational age
FDR	false discovery rate
LMP	last menstrual period
WMHP	Women's Mental Health Program
CANDLE	Conditions Affecting Neurocognitive Development and Learning in Early Childhood

Abbreviations

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