Detecting cord blood cell type-specific epigenetic associations with gestational diabetes mellitus and early childhood growth

Abstract

Background Epigenome-wide association studies (EWAS) have provided opportunities to understand the role of epigenetic mechanisms in development and pathophysiology of many chronic diseases. However, an important limitation of conventional EWAS is that profiles of epigenetic variability are often obtained in samples of mixed cell types. Here, we aim to assess whether changes in cord blood DNA methylation (DNAm) associated with gestational diabetes mellitus (GDM) exposure and early childhood growth markers occur in a cell type-specific manner. Results We analyzed 275 cord blood samples collected at delivery from a prospective pre-birth cohort with genome-wide DNAm profiled by the Illumina MethylationEPIC array. We estimated proportions of seven common cell types in each sample using a cord blood-specific DNAm reference panel. Leveraging a recently developed approach named CellDMC, we performed cell type-specific EWAS to identify CpG loci significantly associated with GDM, or 3-year-old body mass index (BMI) z-score. A total of 1410 CpG loci displayed significant cell type-specific differences in methylation level between 23 GDM cases and 252 controls with a false discovery rate < 0.05. Gene Ontology enrichment analysis indicated that LDL transportation emerged from CpG specifically identified from B-cells DNAm analyses and the mitogen-activated protein kinase pathway emerged from CpG specifically identified from natural killer cells DNAm analyses. In addition, we identified four and six loci associated with 3-year-old BMI z-score that were specific to CD8+ T-cells and monocytes, respectively. By performing genome-wide permutation tests, we validated that most of our detected signals had low false positive rates. Conclusion Compared to conventional EWAS adjusting for the effects of cell type heterogeneity, the proposed approach based on cell type-specific EWAS could provide additional biologically meaningful associations between CpG methylation, prenatal maternal GDM or 3-year-old BMI. With careful validation, these findings may provide new insights into the pathogenesis, programming, and consequences of related childhood metabolic dysregulation. Therefore, we propose that cell type-specific analyses are worth cautious explorations.

Can blood at adult age predict epigenetic changes of the brain during fetal stages?

“…These genes are known markers of bone marrow hematopoietic progenitors, B lymphocytes, and lymphoid progenitor cells in blood, and the same genes are also markers of specific glial cells of the brain [34]. These findings suggested that DNA methylation differences in adult blood have significant concordance with fetal brain, a finding that is consistent with the idea of blood cells as keepers of epigenetic memory of early-life development [35,36]. We also used gene expression data of developing fetal brain of pig from our earlier study [11] to understand effect of the common methylations on gene regulation of brain during fetal development.…”

Nucleated red blood cells explain most of the association between DNA methylation and gestational age

“…As a primary step to explore cell-type specific changes in DNAm with GA, we used the interaction-based algorithm CellDMC that has been validated in several EWAS datasets and data in which the actual cell-type composition is known 24 , 33 , 34 . We identified 2330 differentially methylated CpGs associated with GA, with an overwhelming number of the significant CpGs confined to nRBCs (2030 CpGs linked to 2836 genes).…”

Association of environmental exposure to chromium with differential DNA methylation: An epigenome-wide study

“…However, the similar lifestyles, cultural backgrounds, and socioeconomic status of the participants; the high-quality control procedures; and the Houseman regression calibration method, which accounts for different cell-type compositions, can reduce bias. The epigenetic effect of Cr should be further explored in different cell types because DNA methylation might be specific to certain cell types ( Lu et al, 2021 ).…”