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 Oteo, Dereje D. Jima, Tuomas Kvist, Andrea Baccarelli, Cory White, Faisal I. Rezwan, Gemma C. Sharp, Gwen Tindula, Anna Bergström, Veit Grote, John Dou, Elena Isaevska, Maria C. Magnus, Eva Corpeleijn, Patrice Perron, Vincent W.V. Jaddoe, Ellen A. Nøhr, Léa Maître, María 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, Ãngel Carracedo, Natàlia Ferré, Brenda Eskenazi, Manolis Kogevinas, Tim S. Nawrot, Monica Cheng Munthe‐Kaas, Zdenko Herceg, Caroline L. Relton, Erik Melén, Dariusz Gruszfeld, Carrie V. Breton, M. Daniele 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 Räikkönen, Emily Oken, John W. Holloway, Syed Hasan Arshad, Stephanie J. London, Nina Holland
Abstract
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. 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). 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. 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.