TY - JOUR
T1 - Neonatal DNA methylation patterns associate with gestational age
AU - Schroeder, James W.
AU - Conneely, Karen N.
AU - Cubells, Joseph C.
AU - Kilaru, Varun
AU - Jeffrey Newport, D.
AU - Knight, Bettina T.
AU - Stowe, Zachary N.
AU - Brennan, Patricia A.
AU - Krushkal, Julia
AU - Tylavsky, Frances A.
AU - Taylor, Robert N.
AU - Adkins, Ronald M.
AU - Smith, Alicia K.
N1 - Funding Information:
2.041,42 for the 39 genes that demonstrated evidence of differ-Emory sample collection was supported by the Translational ential methylation in the discovery cohort to evaluate if specific Research Center in Behavioral Sciences (TRCBS; P50 biological processes were enriched in the data set. This web-MH077928) and Specialized Center of Research on Sex and based application matches gene lists with common biological Gender Factors Affecting Women’s Health (P50 MH068036). feature annotations. Significance is determined by enrichment Assay (MH088609) and salary support for A.K.S. (MH085806) of the genes of interest in the context of the known annota-was provided by the National Institute of Mental Health. The tions, and a hypergeometric p value is obtained through an CANDLE Study is supported by the Urban Child Institute. FDR correction. To account for potential limitations in this Molecular assays and analyses in the CANDLE cohort were sup-approach,37we also re-performed this analysis on ten identically ported by the National Institute of Child Health and Human sized gene sets generated by permutation. In each permutation, Development (HD060713, HD055462).
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Arginine vasopressin and oxytocin
KW - Genome-wide DNA methylation
KW - Gestational age
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U2 - 10.4161/epi.6.12.18296
DO - 10.4161/epi.6.12.18296
M3 - Article
C2 - 22139580
AN - SCOPUS:83255193428
VL - 6
SP - 1498
EP - 1504
JO - Epigenetics
JF - Epigenetics
SN - 1559-2294
IS - 12
ER -