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


Olivia Solomon, University of California, Berkeley
Karen Huen, University of California, Berkeley
Paul Yousefi, Bristol Medical SchoolFollow
Leanne K. Küpers, Universitair Medisch Centrum Groningen
Juan R. González, Instituto de Salud Global de Barcelona
Matthew Suderman, Bristol Medical School
Sarah E. Reese, National Institute of Environmental Health Sciences (NIEHS)
Christian M. Page, Norwegian Institute of Public Health
Olena Gruzieva, Karolinska Institutet
Peter Rzehak, Klinikum der Universität München
Lu Gao, University of Southern California
Kelly M. Bakulski, University of Michigan School of Public HealthFollow
Alexei Novoloaca, International Agency for Research on Cancer
Catherine Allard, Centre Hospitalier Universitaire de Sherbrooke
Irene Pappa, Erasmus MC Sophia Children's Hospital
Maria Llambrich, Instituto de Salud Global de Barcelona
Marta Vives, Instituto de Salud Global de Barcelona
Dereje D. Jima, NC State University
Tuomas Kvist, Lääketieteellinen Tiedekunta
Andrea Baccarelli, Mailman School of Public HealthFollow
Cory White, Merck & Co., Inc.
Faisal I. Rezwan, Aberystwyth University
Gemma C. Sharp, Bristol Medical School
Gwen Tindula, University of California, Berkeley
Anna Bergström, Karolinska Institutet
Veit Grote, Klinikum der Universität München
John F. Dou, University of Michigan School of Public Health
Elena Isaevska, Università degli Studi di Torino, Scuola di Medicina
Maria C. Magnus, Norwegian Institute of Public Health
Eva Corpeleijn, Universitair Medisch Centrum Groningen
Patrice Perron, Centre Hospitalier Universitaire de Sherbrooke
Vincent W.V. Jaddoe, Erasmus MC
Ellen A. Nohr, Syddansk Universitet


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.

Publication Title

Mutation Research - Reviews in Mutation Research