Associations between infant sex and DNA methylation across umbilical cord blood, artery, and placenta samples

ABSTRACT

DNA methylation (DNAm) is vulnerable to dysregulation by environmental exposures during epigenetic reprogramming that occurs in embryogenesis. Sexual dimorphism in environmentally induced DNAm dysregulation has been identified and therefore it is important to understand sex-specific DNAm patterns. DNAm at several autosomal sites has been consistently associated with sex in cord blood and placental foetal tissues. However, there is limited research comparing sex-specific DNAm across tissues, particularly differentially methylated regions (DMRs). This study leverages DNAm data measured using the Illumina HumanMethylation450 BeadChip in cord blood (N = 179), placenta (N = 229), and umbilical artery samples (N = 229) in the PRogramming of Intergenerational Stress Mechanisms (PRISM) cohort to identify autosomal DMRs and differentially methylated positions (DMPs). A replication analyses was conducted in an independent cohort (GEO Accession GSE129841). We identified 183, 257, and 419 DMRs and 2119, 2281, and 3405 DMPs (p_Bonferroni < 0.05) in cord blood, placenta, and artery samples, respectively. Thirty-nine DMRs overlapped in all three tissues, overlapping with genes involved in spermatogenesis (NKAPL, PIWIL2 and AURKC) and X–inactivation (LRIF1). In replication analysis, 85% of DMRs overlapped with those identified in PRISM. Overall, DMRs and DMPs had higher methylation levels among females in cord blood and artery samples, but higher methylation levels among males in placenta samples. Further research is necessary to understand biological mechanisms that contribute to differences in sex-specific DNAm signatures across tissues, as well as to determine if sexual dimorphism in the epigenome impacts response to environmental stressors.

KEYWORDS:

• Epigenetics
• DNA methylation
• EWAS
• sex
• birth cohort

Acknowledgments

We would like to thank Dr. Andres Cardenas from the UC Berkeley School of Public Health for his expertise in analytical methods for conducting epigenome-wide association studies.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Anne Bozack: conceptualization, methodology, formal analysis, investigation, writing – original draft, visualization; Elena Colicino: methodology, writing – review & editing; Allan Just: data curation; Robert Wright: writing – review & editing; Andrea Baccarelli: writing – review & editing; Rosalind Wright: conceptualization, writing – review & editing, supervision, project administration, funding acquisition; Alison Lee: conceptualization, writing – review & editing, supervision.

Data Availability

R script for analysis of replication analyses using GEO Accession GSE129841 is available at https://github.com/annebozack/GEO_infant_sex_rep_analysis. Additional data available upon request to the corresponding author.

Supplementary material

Supplemental data for this article can be accessed here

Additional information

Funding

This work was supported by the National Institute of Environmental Health Sciences [R01 ES030302]; National Institute on Minority Health and Health Disparities [R01 MD013310]; National Heart, Lung, and Blood Institute [R01 HL114396]; National Heart, Lung, and Blood Institute [K23 HL135349]; National Heart, Lung, and Blood Institute [R01 HL095606]; The Grant [P30 ES023515] from the National Institute of Environmental Health Sciences.