Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation

Olivia Solomon, Karen Huen*, Paul Yousefi, Leanne K. Küpers, Juan R. González, Matthew Suderman, Sarah E. Reese, Christian M. Page, Olena Gruzieva, Peter Rzehak, Lu Gao, Kelly M. Bakulski, Alexei Novoloaca, Catherine Allard, Irene Pappa, Maria Llambrich, Marta Vives, Dereje D. Jima, Tuomas Kvist, Andrea BaccarelliCory White, Faisal I. Rezwan, Gemma C. Sharp, Gwen Tindula, Anna Bergström, Veit Grote, John F. Dou, Elena Isaevska, Maria C. Magnus, Eva Corpeleijn, Patrice Perron, Vincent W.V. Jaddoe, Ellen A. Nohr, Lea Maitre, Maria Foraster, Cathrine Hoyo, Siri E. Håberg, Jari Lahti, Dawn L. DeMeo, Hongmei Zhang, Wilfried Karmaus, Inger Kull, Berthold Koletzko, Jason I. Feinberg, Luigi Gagliardi, Luigi Bouchard, Cecilia Høst Ramlau-Hansen, Henning Tiemeier, Gillian Santorelli, Rachel L. Maguire, Darina Czamara, Augusto A. Litonjua, Jean Paul Langhendries, Michelle Plusquin, Johanna Lepeule, Elisabeth B. Binder, Elvira Verduci, Terence Dwyer, Ángel Carracedo, Natalia Ferre, Brenda Eskenazi, Manolis Kogevinas, Tim S. Nawrot, Monica C. Munthe-Kaas, Zdenko Herceg, Caroline Relton, Erik Melén, Dariusz Gruszfeld, Carrie Breton, M. D. Fallin, Akram Ghantous, Wenche Nystad, Barbara Heude, Harold Snieder, Marie France Hivert, Janine F. Felix, Thorkild I.A. Sørensen, Mariona Bustamante, Susan K. Murphy, Katri Raikkönen, Emily Oken, John W. Holloway, Syed Hasan Arshad, Stephanie J. London, Nina Holland

*Corresponding author for this work

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Abstract

Background: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits.

Methods: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5–10 years from 8 cohorts (n = 4268).

Results: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10−7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10−6) in older children and had methylation differences in the same direction.

Conclusions: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.

Original languageEnglish
Article number108415
Number of pages10
JournalMutation Research - Reviews in Mutation Research
Volume789
DOIs
Publication statusPublished - 1-Jan-2022

Keywords

  • Children
  • Cord blood
  • DNA methylation
  • EWAS
  • Sex

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