Genomic and molecular characterization of preterm birth

Abstract

Preterm birth (PTB) complications are the leading cause of long-term morbidity and mortality in children. By using whole blood samples, we integrated whole-genome sequencing (WGS), RNA sequencing (RNA-seq), and DNA methylation data for 270 PTB and 521 control families. We analyzed this combined dataset to identify genomic variants associated with PTB and secondary analyses to identify variants associated with very early PTB (VEPTB) as well as other subcategories of disease that may contribute to PTB. We identified differentially expressed genes (DEGs) and methylated genomic loci and performed expression and methylation quantitative trait loci analyses to link genomic variants to these expression and methylation changes. We performed enrichment tests to identify overlaps between new and known PTB candidate gene systems. We identified 160 significant genomic variants associated with PTB-related phenotypes. The most significant variants, DEGs, and differentially methylated loci were associated with VEPTB. Integration of all data types identified a set of 72 candidate biomarker genes for VEPTB, encompassing genes and those previously associated with PTB. Notably, PTB-associated genes RAB31 and RBPJ were identified by all three data types (WGS, RNA-seq, and methylation). Pathways associated with VEPTB include EGFR and prolactin signaling pathways, inflammation- and immunity-related pathways, chemokine signaling, IFN-γ signaling, and Notch1 signaling. Progress in identifying molecular components of a complex disease is aided by integrated analyses of multiple molecular data types and clinical data. With these data, and by stratifying PTB by subphenotype, we have identified associations between VEPTB and the underlying biology.

Replicated Umbilical Cord Blood DNA Methylation Loci Associated with Gestational Age at Birth

“…28,30 The first 40 weeks of this distribution has, of course, been targeted as a critical period in establishment of the utero-placental interface, embryonic development and transmission of signal to initiate labor onset. Investigators have observed a direct association of GA on newborn/umbilical cord DNAm 43,60,68,71,84 , including supervised algorithms designed to predict GA. 10,36,42 These studies are consistent with integrative approaches that have shown involvement of inflammatory and immune-related pathways 4,22,37 , and the larger picture of these pathways as being integral to the onset of labor. 65,66,73 Of the many potential antecedents, the literature defines a strong pathophysiological link for the causal role of inflammation on preterm birth.…”

Single Cell Transcriptional Signatures of the Human Placenta in Term and Preterm Parturition

“…To demonstrate the translational value of single-cell RNA signatures derived from the placenta, we conducted an in silico analysis in public datasets 58, 59 to test whether the single-cell signatures could be non-invasively monitored in the maternal circulation throughout gestation (Figure 4A). Previous studies have correlated bulk mRNA expression in the maternal circulation with gestational age at blood draw 58, 60 , risk for preterm birth 59, 61–63 , or both 64, 65 . First, we showed that the single-cell signatures of macrophages, monocytes, NK cells, T cells, npiCTB, and fibroblasts are modulated throughout gestation in the maternal circulation (Figure 4B-C, S19A).…”

Epigenome Wide Association and Stochastic Epigenetic Mutation Analysis on Cord Blood of Preterm Birth

“…Recent findings in cord blood, identified more than 8800 CpG sites associated with gestational age and the pathway analyses identified enrichment for biological processes critical to embryonic development of brain and lung tissue [ 10 ]. Moreover, several studies analyzed cord blood DNA methylation levels comparing preterm and full-term babies and reported a great number of significant differences even if the consistence among these studies has not been evaluated yet [ 11 , 12 , 13 , 14 , 15 ]. Considering the strong background regarding a potential role of epigenetics in PTB, the aim of the present study was to investigate DNA methylation differences associated with PTB at genome wide level and to evaluate consistency of results published so far.…”