Allele-resolved methylome and transcriptome in cord blood from growth-restricted and normally-grown newborns — ASN Events
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Allele-resolved methylome and transcriptome in cord blood from growth-restricted and normally-grown newborns (#503)

Alicja J Andraszek 1 , Kylie Crawford 1 2 , Jesrine Hong 1 2 3 , Sailesh Kumar 1 2 4 5 , Sandra R Richardson 1 , Adam D Ewing 1
  1. Mater Research Insitute - University of Queensland, Brisbane, Queensland, Australia
  2. The University of Queensland School of Medicine, Brisbane, Queensland, Australia
  3. Universiti Malaya Faculty of Medicine Department of Obstetrics and Gynecology, Kuala Lumpur, Malaysia
  4. Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
  5. NHMRC Centre for Research Excellence in Stillbirth, Brisbane, Queensland, Australia

Background: Fetal growth restriction is a major driver of neonatal mortality and morbidity and adverse long-term outcomes. Placental and cord blood research conducted in growth restriction to-date has primarily utilised methylation arrays, limiting discovery to pre-set CpG sites and masking allele-specific differences in methylation. In this discovery genomics case-control study, we aimed to analyse full-genome CpG methylation in cord blood samples with linkage to clinical, transcriptome, and placental methylation data.

Methods: We analysed cord whole blood from twelve cases of fetal growth restriction and twelve appropriate for gestational age controls. We excluded neonates with chromosomal or major congenital abnormalities. Whole-genome sequencing was conducted to 20X coverage on the PromethION and basecalled with a model identifying 5-methylcytosine and 5-hydroxymethylcytosine. Paired placenta samples were sequenced in-parallel for six of the cases and six controls. Further cord transcriptome sequencing was also conducted for a subset of neonates with available PAXgene RNA samples. Total RNA was enriched for mRNA, reverse-transcribed, and sequenced on the PromethION. Transcriptome data will be analysed for differential expression, including allele-specific expression, and the presence of novel transcript isoforms. Cell type proportions, epigenetic age, and involved pathways will be estimated based on these data.

Results: Cord blood exhibited 83% mean methylation at CpG sites. A shift towards global hypomethylation (73-82% mean methylation) was observed in 5/12 growth-restricted and 1/12 non-restricted neonates, correlating with increased proportion of nucleated red blood cells in clinical blood tests. 35 putative differentially methylated regions above threshold and post-hoc T-test P < 0.05 were identified between cases and controls in males, and 19 regions were identified in females. There was no significant correlation between cord and placental methylomes in paired samples. 

Conclusion: This study represents the first profiling of the human cord blood methylome in a cohort to allele-resolution across the whole genome.