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An epigenetic clock for gestational age at birth based on blood methylation data.

ABSTRACT: Gestational age is often used as a proxy for developmental maturity by clinicians and researchers alike. DNA methylation has previously been shown to be associated with age and has been used to accurately estimate chronological age in children and adults. In the current study, we examine whether DNA methylation in cord blood can be used to estimate gestational age at birth.We find that gestational age can be accurately estimated from DNA methylation of neonatal cord blood and blood spot samples. We calculate a DNA methylation gestational age using 148 CpG sites selected through elastic net regression in six training datasets. We evaluate predictive accuracy in nine testing datasets and find that the accuracy of the DNA methylation gestational age is consistent with that of gestational age estimates based on established methods, such as ultrasound. We also find that an increased DNA methylation gestational age relative to clinical gestational age is associated with birthweight independent of gestational age, sex, and ancestry.DNA methylation can be used to accurately estimate gestational age at or near birth and may provide additional information relevant to developmental stage. Further studies of this predictor are warranted to determine its utility in clinical settings and for research purposes. When clinical estimates are available this measure may increase accuracy in the testing of hypotheses related to developmental age and other early life circumstances.

SUBMITTER: Knight AK

PROVIDER: S-EPMC5054584 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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An epigenetic clock for gestational age at birth based on blood methylation data.

Knight Anna K AK Craig Jeffrey M JM Theda Christiane C Bækvad-Hansen Marie M Bybjerg-Grauholm Jonas J Hansen Christine S CS Hollegaard Mads V MV Hougaard David M DM Mortensen Preben B PB Weinsheimer Shantel M SM Werge Thomas M TM Brennan Patricia A PA Cubells Joseph F JF Newport D Jeffrey DJ Stowe Zachary N ZN Cheong Jeanie L Y JL Dalach Philippa P Doyle Lex W LW Loke Yuk J YJ Baccarelli Andrea A AA Just Allan C AC Wright Robert O RO Téllez-Rojo Mara M MM Svensson Katherine K Trevisi Letizia L Kennedy Elizabeth M EM Binder Elisabeth B EB Iurato Stella S Czamara Darina D Räikkönen Katri K Lahti Jari M T JM Pesonen Anu-Katriina AK Kajantie Eero E Villa Pia M PM Laivuori Hannele H Hämäläinen Esa E Park Hea Jin HJ Bailey Lynn B LB Parets Sasha E SE Kilaru Varun V Menon Ramkumar R Horvath Steve S Bush Nicole R NR LeWinn Kaja Z KZ Tylavsky Frances A FA Conneely Karen N KN Smith Alicia K AK

Genome biology 20161007 1

<h4>Background</h4>Gestational age is often used as a proxy for developmental maturity by clinicians and researchers alike. DNA methylation has previously been shown to be associated with age and has been used to accurately estimate chronological age in children and adults. In the current study, we examine whether DNA methylation in cord blood can be used to estimate gestational age at birth.<h4>Results</h4>We find that gestational age can be accurately estimated from DNA methylation of neonatal ...[more]

PMID: 27717399

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Project description:BackgroundHow epigenetic modifications of DNA are associated with gestational age at birth is not fully understood. We investigated potential effects of differential paternal DNA methylation (DNAm) on offspring gestational age at birth by conducting an epigenome-wide search for cytosine-phosphate-guanine (CpG) sites.MethodsStudy participants in this study consist of male cohort members or partners of the F1-generation of the Isle of Wight Birth Cohort (IoWBC). DNAm levels in peripheral blood from F1-fathers (n = 92) collected around pregnancy of their spouses were analyzed using the Illumina 450K array. A 5-step statistical analysis was performed. First, a training-testing screening approach was applied to select CpG sites that are potentially associated with gestational age at birth. Second, functional enrichment analysis was employed to identify biological processes. Third, by centralizing on biologically informative genes, Cox proportional hazards models were used to assess the hazard ratios of individual paternal CpGs on gestational age adjusting for confounders. Fourth, to assess the validity of our results, we compared our CpG-gestational age correlations within a Born into Life Study in Sweden (n = 15). Finally, we investigated the correlation between the detected CpGs and differential gene expression in F2 cord blood in the IoWBC.ResultsAnalysis of DNAm of fathers collected around their partner's pregnancy identified 216 CpG sites significantly associated with gestational age at birth. Functional enrichment pathways analyses of the annotated genes revealed 2 biological pathways significantly related to cell-cell membrane adhesion molecules. Differential methylation of 9 cell membrane adhesion pathway-related CpGs were significantly associated with gestational age at birth after adjustment for confounders. The replication sample showed correlation coefficients of 2 pathway-related CpGs with gestational age at birth within 95% confidence intervals of correlation coefficients in IoWBC. Finally, CpG sites of protocadherin (PCDH) gene clusters were associated with gene expression of PCDH in F2 cord blood.ConclusionsOur findings suggest that differential paternal DNAm may affect gestational age at birth through cell-cell membrane adhesion molecules. The results are novel but require future replication in a larger cohort.

Dataset Information

An epigenetic clock for gestational age at birth based on blood methylation data.

Publications

An epigenetic clock for gestational age at birth based on blood methylation data.

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