Sex differences in DNA methylation across gestation: a large scale, cross-cohort, multi-tissue analysis
Year: 2024
Type: article
Study design: Observational Study
Abstract: Biological sex is a key variable influencing many physiological systems. Disease prevalence as well as treatment success can be modified by sex. Differences emerge already early in life and include pregnancy complications and adverse birth outcomes. The placenta is a critical organ for fetal development and shows sex-based differences in the expression of hormones and cytokines. Epigenetic regulation, such as DNA methylation (DNAm), may underlie the previously reported placental sexual dimorphism. We associated placental DNAm with fetal sex in three cohorts. Individual cohort results were meta-analyzed with random-effects modelling. CpG-sites differentially methylated with sex were further investigated regarding pathway enrichment, overlap with methylation quantitative trait loci (meQTLs), and hits from phenome-wide association studies (PheWAS). We evaluated the consistency of findings across tissues (CVS, i.e. chorionic villus sampling from early placenta, and cord blood) as well as with gene expression. We identified 10,320 epigenome-wide significant sex-differentially methylated probes (DMPs) spread throughout the epigenome of the placenta at birth. Most DMPs presented with lower DNAm levels in females. DMPs mapped to genes upregulated in brain, were enriched for neurodevelopmental pathways and significantly overlapped with meQTLs and PheWAS hits. Effect sizes were moderately correlated between CVS and placenta at birth, but only weakly correlated between birth placenta and cord blood. Sex differential gene expression in birth placenta was less pronounced and implicated genetic regions only marginally overlapped with those associated with differential DNAm. Our study provides an integrative perspective on sex-differential DNAm in perinatal tissues underscoring the possible link between placenta and brain.
Institutions: Max Planck Institute of Psychiatry, University of Helsinki, Finnish Institute for Health and Welfare, The Queen's Medical Research Institute, University of Edinburgh, Karolinska Institutet, Humboldt-Universität zu Berlin, Charité – Universitätsmedizin Berlin, Helsinki University Hospital, Emory University, University of California, Irvine
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,290
Awards: G3670652582, G3837860024, Parental Mental Disorders in the Etiology of Offspring Mental Disorders: Sensitive Periods and Mediating Biological Pathways. A Cross-Cohort Study among over 500000 Participants., G5048279094, Understanding, predicting, and treating depression in pregnancy to improve mothers and offspring mental health outcomes, G539686318, G5650571161, G5891953159, G7333280071, G7759067878, G8074060860
OpenAlex ID: W4394676423