Genome-wide DNA methylation associations with spontaneous preterm birth in US blacks: findings in maternal and cord blood samples

Abstract

Preterm birth (PTB) affects one in six Black babies in the United States. Epigenetics is believed to play a role in PTB; however, only a limited number of epigenetic studies of PTB have been reported, most of which have focused on cord blood DNA methylation (DNAm) and/or were conducted in white populations. Here we conducted, by far, the largest epigenome-wide DNAm analysis in 300 Black women who delivered early spontaneous preterm (sPTB, n = 150) or full-term babies (n = 150) and replicated the findings in an independent set of Black mother-newborn pairs from the Boston Birth Cohort. DNAm in maternal blood and/or cord blood was measured using the Illumina HumanMethylation450 BeadChip. We identified 45 DNAm loci in maternal blood associated with early sPTB, with a false discovery rate (FDR) <5%. Replication analyses confirmed sPTB associations for cg03915055 and cg06804705, located in the promoter regions of the CYTIP and LINC00114 genes, respectively. Both loci had comparable associations with early sPTB and early medically-indicated PTB, but attenuated associations with late sPTB. These associations could not be explained by cell composition, gestational complications, and/or nearby maternal genetic variants. Analyses in the newborns of the 110 Black women showed that cord blood methylation levels at both loci had no associations with PTB. The findings from this study underscore the role of maternal DNAm in PTB risk, and provide a set of maternal loci that may serve as biomarkers for PTB. Longitudinal studies are needed to clarify temporal relationships between maternal DNAm and PTB risk.

Association between one-carbon metabolism indices and DNA methylation status in maternal and cord blood

“…Few studies have examined changes in DNA methylation in maternal blood over pregnancy 31 – 34 . One recent study identified 45 CpG sites associated with spontaneous preterm birth, which may reflect DNA methylation changes occurring in the weeks between preterm and term birth 34 . However, only two of these CpG sites were both replicated and validated in an independent cohort 34 .…”

“…One recent study identified 45 CpG sites associated with spontaneous preterm birth, which may reflect DNA methylation changes occurring in the weeks between preterm and term birth 34 . However, only two of these CpG sites were both replicated and validated in an independent cohort 34 . Identification of CpG sites whose methylation levels change over pregnancy may result in better characterization of the genes and pathways involved in maintaining a healthy, uncomplicated pregnancy.…”

Maternal smoking during pregnancy and cord blood DNA methylation: new insight on sex differences and effect modification by maternal folate levels

“…Using the R/Bioconductor package 'minfi', [48] we performed several quality control steps as we reported previously [49]. After examining the 450K control probes to assess bisulfite conversion, extension, hybridization, staining, and others, we plotted the median for both Meth and Unmeth intensity signals for each array to identify poorly performing arrays, and then checked for sex discrepancies by comparing self-reported sex against data-derived sex values.…”

“…The procedure for genome-wide methylation profiling, data cleaning, and processing in maternal blood samples, similar to that described above for cord blood samples, has been reported elsewhere [49]. These procedures led to 290 maternal samples for subsequent analyses [49].…”

“…The procedure for genome-wide methylation profiling, data cleaning, and processing in maternal blood samples, similar to that described above for cord blood samples, has been reported elsewhere [49]. These procedures led to 290 maternal samples for subsequent analyses [49]. For the current study, we removed 26 mothers who quit smoking during pregnancy and 12 with missing data on smoking during pregnancy, leaving the focus of our analyses on 252 maternal samples.…”