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 Baccarelli; Cory 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

doi:10.1016/j.mrrev.2022.108415

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

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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.

Iaith wreiddiol	Saesneg
Rhif yr erthygl	108415
Cyfnodolyn	Mutation Research - Reviews in Mutation Research
Cyfrol	789
Dyddiad ar-lein cynnar	22 Maw 2022
Dynodwyr Gwrthrych Digidol (DOIs)	https://doi.org/10.1016/j.mrrev.2022.108415
Statws	Cyhoeddwyd - 12 Meh 2022

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Mae’r allbwn hwn yn cyfrannu at y Nod(au) Datblygu Cynaliadwy canlynol

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10.1016/j.mrrev.2022.108415Trwydded: CC BY-NC-ND

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Solomon, O., Huen, K., Yousefi, P., Küpers, L. K., González, J. R., Suderman, M., Reese, S. E., Page, C. M., Gruzieva, O., Rzehak, P., Gao, L., Bakulski, K. M., Novoloaca, A., Allard, C., Pappa, I., Llambrich, M., Vives, M., Jima, D. D., Kvist, T., ... Maguire, R. L. (2022). Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation. Mutation Research - Reviews in Mutation Research, 789, erthygl 108415. https://doi.org/10.1016/j.mrrev.2022.108415

@article{9c3fec58fded411a9e053c6503ab39bf,

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

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.",

keywords = "DNA methylation, Sex, Children, Cord blood, EWAS, GENE, EXPRESSION, GENDER, INFORMATION, PREGNANCY, PACKAGE, Epigenomics, Epigenesis, Genetic, Humans, DNA Methylation/genetics, Male, Sex Characteristics, Pregnancy, Adolescent, Female, Epigenome, Child, Infant, Newborn",

author = "Olivia Solomon and Karen Huen and Paul Yousefi and K{\"u}pers, {Leanne K.} and Gonz{\'a}lez, {Juan R.} and Matthew Suderman and Reese, {Sarah E.} and Page, {Christian M.} and Olena Gruzieva and Peter Rzehak and Lu Gao and Bakulski, {Kelly M.} and Alexei Novoloaca and Catherine Allard and Irene Pappa and Maria Llambrich and Marta Vives and Jima, {Dereje D.} and Tuomas Kvist and Andrea Baccarelli and Cory White and Rezwan, {Faisal I.} and Sharp, {Gemma C.} and Gwen Tindula and Anna Bergstr{\"o}m and Veit Grote and Dou, {John F.} and Elena Isaevska and Magnus, {Maria C.} and Eva Corpeleijn and Patrice Perron and Jaddoe, {Vincent W.V.} and Nohr, {Ellen A.} and Lea Maitre and Maria Foraster and Cathrine Hoyo and H{\aa}berg, {Siri E.} and Jari Lahti and DeMeo, {Dawn L.} and Hongmei Zhang and Wilfried Karmaus and Inger Kull and Berthold Koletzko and Feinberg, {Jason I.} and Luigi Gagliardi and Luigi Bouchard and Ramlau-Hansen, {Cecilia H{\o}st} and Henning Tiemeier and Gillian Santorelli and Maguire, {Rachel L.}",

year = "2022",

month = jun,

day = "12",

doi = "10.1016/j.mrrev.2022.108415",

language = "English",

volume = "789",

journal = "Mutation Research - Reviews in Mutation Research",

issn = "1388-2139",

publisher = "Elsevier",

}

Solomon, O, Huen, K, Yousefi, P, Küpers, LK, González, JR, Suderman, M, Reese, SE, Page, CM, Gruzieva, O, Rzehak, P, Gao, L, Bakulski, KM, Novoloaca, A, Allard, C, Pappa, I, Llambrich, M, Vives, M, Jima, DD, Kvist, T, Baccarelli, A, White, C, Rezwan, FI, Sharp, GC, Tindula, G, Bergström, A, Grote, V, Dou, JF, Isaevska, E, Magnus, MC, Corpeleijn, E, Perron, P, Jaddoe, VWV, Nohr, EA, Maitre, L, Foraster, M, Hoyo, C, Håberg, SE, Lahti, J, DeMeo, DL, Zhang, H, Karmaus, W, Kull, I, Koletzko, B, Feinberg, JI, Gagliardi, L, Bouchard, L, Ramlau-Hansen, CH, Tiemeier, H, Santorelli, G & Maguire, RL 2022, 'Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation', Mutation Research - Reviews in Mutation Research, cyfrol. 789, 108415. https://doi.org/10.1016/j.mrrev.2022.108415

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.

PY - 2022/6/12

Y1 - 2022/6/12

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 - DNA methylation

KW - Sex

KW - Children

KW - Cord blood

KW - EWAS

KW - GENE

KW - EXPRESSION

KW - GENDER

KW - INFORMATION

KW - PREGNANCY

KW - PACKAGE

KW - Epigenomics

KW - Epigenesis, Genetic

KW - Humans

KW - DNA Methylation/genetics

KW - Male

KW - Sex Characteristics

KW - Pregnancy

KW - Adolescent

KW - Female

KW - Epigenome

KW - Child

KW - Infant, Newborn

UR - http://www.scopus.com/inward/record.url?scp=85126865473&partnerID=8YFLogxK

U2 - 10.1016/j.mrrev.2022.108415

DO - 10.1016/j.mrrev.2022.108415

M3 - Review Article

C2 - 35690418

SN - 1388-2139

VL - 789

JO - Mutation Research - Reviews in Mutation Research

JF - Mutation Research - Reviews in Mutation Research

M1 - 108415

ER -

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

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