TY - JOUR

T1 - Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation

AU - Solomon, Olivia

AU - Huen, Karen

AU - Yousefi, Paul

AU - Küpers, Leanne K.

AU - González, Juan R.

AU - Suderman, Matthew

AU - Reese, Sarah E.

AU - Page, Christian M.

AU - Gruzieva, Olena

AU - Rzehak, Peter

AU - Gao, Lu

AU - Bakulski, Kelly M.

AU - Novoloaca, Alexei

AU - Allard, Catherine

AU - Pappa, Irene

AU - Llambrich, Maria

AU - Vives, Marta

AU - Jima, Dereje D.

AU - Kvist, Tuomas

AU - Baccarelli, Andrea

AU - White, Cory

AU - Rezwan, Faisal I.

AU - Sharp, Gemma C.

AU - Tindula, Gwen

AU - Bergström, Anna

AU - Grote, Veit

AU - Dou, John F.

AU - Isaevska, Elena

AU - Magnus, Maria C.

AU - Corpeleijn, Eva

AU - Perron, Patrice

AU - Jaddoe, Vincent W.V.

AU - Nohr, Ellen A.

AU - Maitre, Lea

AU - Foraster, Maria

AU - Hoyo, Cathrine

AU - Håberg, Siri E.

AU - Lahti, Jari

AU - DeMeo, Dawn L.

AU - Zhang, Hongmei

AU - Karmaus, Wilfried

AU - Kull, Inger

AU - Koletzko, Berthold

AU - Feinberg, Jason I.

AU - Gagliardi, Luigi

AU - Bouchard, Luigi

AU - Ramlau-Hansen, Cecilia Høst

AU - Tiemeier, Henning

AU - Santorelli, Gillian

AU - Maguire, Rachel L.

AU - Czamara, Darina

AU - Litonjua, Augusto A.

AU - Langhendries, Jean Paul

AU - Plusquin, Michelle

AU - Lepeule, Johanna

AU - Binder, Elisabeth B.

AU - Verduci, Elvira

AU - Dwyer, Terence

AU - Carracedo, Ángel

AU - Ferre, Natalia

AU - Eskenazi, Brenda

AU - Kogevinas, Manolis

AU - Nawrot, Tim S.

AU - Munthe-Kaas, Monica C.

AU - Herceg, Zdenko

AU - Relton, Caroline

AU - Melén, Erik

AU - Gruszfeld, Dariusz

AU - Breton, Carrie

AU - Fallin, M. D.

AU - Ghantous, Akram

AU - Nystad, Wenche

AU - Heude, Barbara

AU - Snieder, Harold

AU - Hivert, Marie France

AU - Felix, Janine F.

AU - Sørensen, Thorkild I.A.

AU - Bustamante, Mariona

AU - Murphy, Susan K.

AU - Raikkönen, Katri

AU - Oken, Emily

AU - Holloway, John W.

AU - Arshad, Syed Hasan

AU - London, Stephanie J.

AU - Holland, Nina

N1 - Publisher Copyright: © 2022 The Authors

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - Children

KW - Cord blood

KW - DNA methylation

KW - EWAS

KW - Sex

U2 - 10.1016/j.mrrev.2022.108415

DO - 10.1016/j.mrrev.2022.108415

M3 - Review

C2 - 35690418

AN - SCOPUS:85126865473

VL - 789

JO - Mutation Research - Reviews

JF - Mutation Research - Reviews

SN - 1383-5742

M1 - 108415

ER -