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

doi:10.1016/j.mrrev.2022.108415

Review

. 2022 Jan-Jun:789:108415.

doi: 10.1016/j.mrrev.2022.108415. Epub 2022 Mar 14.

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

Olivia Solomon¹, Karen Huen², Paul Yousefi³, Leanne K Küpers⁴, Juan R González⁵, Matthew Suderman⁶, Sarah E Reese⁷, Christian M Page⁸, Olena Gruzieva⁹, Peter Rzehak¹⁰, Lu Gao¹¹, Kelly M Bakulski¹², Alexei Novoloaca¹³, Catherine Allard¹⁴, Irene Pappa¹⁵, Maria Llambrich⁵, Marta Vives¹⁶, Dereje D Jima¹⁷, Tuomas Kvist¹⁸, Andrea Baccarelli¹⁹, Cory White²⁰, Faisal I Rezwan²¹, Gemma C Sharp⁶, Gwen Tindula¹, Anna Bergström⁹, Veit Grote¹⁰, John F Dou¹², Elena Isaevska²², Maria C Magnus²³, Eva Corpeleijn⁴, Patrice Perron²⁴, Vincent W V Jaddoe²⁵, Ellen A Nohr²⁶, Lea Maitre⁵, Maria Foraster²⁷, Cathrine Hoyo²⁸, Siri E Håberg²³, Jari Lahti¹⁸, Dawn L DeMeo²⁹, Hongmei Zhang³⁰, Wilfried Karmaus³⁰, Inger Kull³¹, Berthold Koletzko¹⁰, Jason I Feinberg³², Luigi Gagliardi³³, Luigi Bouchard³⁴, Cecilia Høst Ramlau-Hansen³⁵, Henning Tiemeier³⁶, Gillian Santorelli³⁷, Rachel L Maguire³⁸, Darina Czamara³⁹, Augusto A Litonjua⁴⁰, Jean-Paul Langhendries⁴¹, Michelle Plusquin⁴², Johanna Lepeule⁴³, Elisabeth B Binder⁴⁴, Elvira Verduci⁴⁵, Terence Dwyer⁴⁶, Ángel Carracedo⁴⁷, Natalia Ferre⁴⁸, Brenda Eskenazi⁴⁹, Manolis Kogevinas⁵⁰, Tim S Nawrot⁵¹, Monica C Munthe-Kaas⁵², Zdenko Herceg¹³, Caroline Relton⁶, Erik Melén³¹, Dariusz Gruszfeld⁵³, Carrie Breton¹¹, M D Fallin³², Akram Ghantous¹³, Wenche Nystad⁵⁴, Barbara Heude⁵⁵, Harold Snieder⁴, Marie-France Hivert⁵⁶, Janine F Felix²⁵, Thorkild I A Sørensen⁵⁷, Mariona Bustamante⁵, Susan K Murphy⁵⁸, Katri Raikkönen¹⁸, Emily Oken⁵⁹, John W Holloway⁶⁰, Syed Hasan Arshad⁶¹, Stephanie J London⁷, Nina Holland¹

Affiliations

¹ Children's Environmental Health Laboratory, Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, USA.
² Children's Environmental Health Laboratory, Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, USA. Electronic address: khuen@berkeley.edu.
³ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, BS8 2BN, UK.
⁴ University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands.
⁵ ISGlobal, Barcelona Institute for Global Health, Dr Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
⁶ MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, BS8 2BN, UK.
⁷ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA.
⁸ Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway; Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway.
⁹ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Center for Occupational and Environmental Medicine, Region Stockholm, Sweden.
¹⁰ Div. Metabolic and Nutritional Medicine, Dept. Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians Universität München (LMU), Munich, Germany.
¹¹ Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90089, USA.
¹² School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
¹³ International Agency for Research on Cancer, Lyon, France.
¹⁴ Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, QC, Canada.
¹⁵ Department of Child and Adolescent Psychiatry/ Psychology, Erasmus Medical Center, Sophia Children's Hospital, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands; The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands.
¹⁶ ISGlobal, Barcelona Institute for Global Health, Dr Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.
¹⁷ Center for Human Health and the Environment, North Carolina State University, Raleigh, NC 27606, USA; Bioinformatics Research Center, North Carolina State University, Raleigh, NC 27606, USA.
¹⁸ Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Finland.
¹⁹ Laboratory of Precision Environmental Biosciences, Columbia University Mailman School of Public Health, New York, NY, USA.
²⁰ Merck Exploratory Science Center, Merck Research Laboratories, Cambridge, MA 02141, USA.
²¹ Department of Computer Science, Aberystwyth University, Aberystwyth, Ceredigion, SY23 3DB, United Kingdom; Human Development and Health, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
²² Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin, Turin, Italy.
²³ Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
²⁴ Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, QC, Canada; Department of Medicine, Universite de Sherbrooke, QC, Canada.
²⁵ The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands; Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands.
²⁶ Institute of Clinical Research, University of Southern Denmark, Odense, Denmark; Centre of Women's, Family and Child Health, University of South-Eastern Norway, Kongsberg, Norway.
²⁷ ISGlobal, Barcelona Institute for Global Health, Dr Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; PHAGEX Research Group, Blanquerna School of Health Science, Universitat Ramon Llull, Barcelona, Spain.
²⁸ Center for Human Health and the Environment, North Carolina State University, Raleigh, NC 27606, USA; Department of Biological Sciences, North Carolina State University, NC, USA.
²⁹ Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
³⁰ Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, Memphis, USA.
³¹ Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; Sachs' Children and Youth Hospital, Södersjukhuset, Stockholm, Sweden.
³² Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
³³ Department of Woman and Child Health, Ospedale Versilia, Azienda USL Toscana Nord Ovest, Viareggio, Italy.
³⁴ Department of Biochemistry and Functional Genomics, Université de Sherbrooke, QC, Canada; Department of Medical Biology, CIUSSS Saguenay-Lac-Saint-Jean, Chicoutimi Hospital, Saguenay, QC, Canada.
³⁵ Department of Public Health, Research Unit for Epidemiology, Aarhus University, 8000 Aarhus C, Denmark.
³⁶ Department of Child and Adolescent Psychiatry/ Psychology, Erasmus Medical Center, Sophia Children's Hospital, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands; Department of Social and Behavioral Science, Harvard TH Chan School of Public Health, 677 Huntington Ave, Boston, MA, USA.
³⁷ Bradford Institute of Health Research, Bradford Royal Infirmary, Bradford BD9 6RJ, UK.
³⁸ Department of Biological Sciences, North Carolina State University, NC, USA; Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27701, USA.
³⁹ Dept. Translational Research in Psychiatry, Max-Planck-Institute of Psychiatry, Munich, Germany.
⁴⁰ Division of Pediatric Pulmonology, Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, USA.
⁴¹ CHC, St Vincent, Liège-Rocourt, Belgium.
⁴² Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium.
⁴³ Univ. Grenoble Alpes, Inserm, CNRS, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, IAB, 38000 Grenoble, France.
⁴⁴ Dept. Translational Research in Psychiatry, Max-Planck-Institute of Psychiatry, Munich, Germany; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, USA.
⁴⁵ Department of Pediatrics, Ospedale dei Bambini Vittore Buzzi, University of Milan, Milan, Italy; Department of Health Sciences, University of Milan, Milan, Italy.
⁴⁶ Clinical Sciences, Heart Group, Murdoch Children's Research Institute, Melbourne, Australia; Department of Pediatrics, University of Melbourne, Melbourne, Australia; Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, UK.
⁴⁷ Grupo de Medicina Xenómica, Fundación Pública Galega de Merdicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), SERGAS, Santiago de Compostela, Spain; Centro de Investigación en Red de Enfermedades Raras (CIBERER) y Centro Nacional de Genotipado (CEGEN-PRB3), Universidad de Santiago de Compostela, Santiago de Compostela, Spain.
⁴⁸ Pediatric Nutrition and Human Development Research Unit, Universitat Rovira i Virgili, IISPV, Reus, Spain.
⁴⁹ Center for Environmental Research and Children's Health, School of Public Health, University of California, Berkeley, CA, USA.
⁵⁰ ISGlobal, Barcelona Institute for Global Health, Dr Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; IMIM (Hospital del Mar Medical Research Institute), Carrer del Dr. Aiguader 88, 08003 Barcelona, Spain.
⁵¹ Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium; Department Public Health & Primary care, Leuven University, Belgium.
⁵² Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway; Department of Pediatric Oncology and Hematology, Oslo University Hospital, Norway.
⁵³ Neonatal Department, Children's Memorial Health Institute, Warsaw, Poland.
⁵⁴ Department of Chronic Diseases and Ageing, Division of Mental and Physical Health, Norwegian Institute of Public Health, Oslo, Norway.
⁵⁵ Université de Paris, Centre for Research in Epidemiology and Statistics (CRESS), INSERM, INRAE, F-75004 Paris, France.
⁵⁶ Department of Medicine, Universite de Sherbrooke, QC, Canada; Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, MA, USA; Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
⁵⁷ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, BS8 2BN, UK; Department of Public Health, Section of Epidemiology, University of Copenhagen, Copenhagen, Denmark; The Novo Nordisk Foundation Center for Basic Metabolic Research, Section on Metabolic Genetics, Faculty of Medical and Health Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵⁸ Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27701, USA.
⁵⁹ Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, MA, USA.
⁶⁰ Human Development and Health, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
⁶¹ Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK; David Hide Asthma and Allergy Research Centre, Isle of Wight, UK.

PMID: 35690418
PMCID: PMC9623595
DOI: 10.1016/j.mrrev.2022.108415

Review

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

Olivia Solomon et al. Mutat Res Rev Mutat Res. 2022 Jan-Jun.

. 2022 Jan-Jun:789:108415.

doi: 10.1016/j.mrrev.2022.108415. Epub 2022 Mar 14.

Authors

Affiliations

¹ Children's Environmental Health Laboratory, Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, USA.
² Children's Environmental Health Laboratory, Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, USA. Electronic address: khuen@berkeley.edu.
³ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, BS8 2BN, UK.
⁴ University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands.
⁵ ISGlobal, Barcelona Institute for Global Health, Dr Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
⁶ MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, BS8 2BN, UK.
⁷ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA.
⁸ Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway; Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway.
⁹ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Center for Occupational and Environmental Medicine, Region Stockholm, Sweden.
¹⁰ Div. Metabolic and Nutritional Medicine, Dept. Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians Universität München (LMU), Munich, Germany.
¹¹ Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90089, USA.
¹² School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
¹³ International Agency for Research on Cancer, Lyon, France.
¹⁴ Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, QC, Canada.
¹⁵ Department of Child and Adolescent Psychiatry/ Psychology, Erasmus Medical Center, Sophia Children's Hospital, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands; The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands.
¹⁶ ISGlobal, Barcelona Institute for Global Health, Dr Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.
¹⁷ Center for Human Health and the Environment, North Carolina State University, Raleigh, NC 27606, USA; Bioinformatics Research Center, North Carolina State University, Raleigh, NC 27606, USA.
¹⁸ Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Finland.
¹⁹ Laboratory of Precision Environmental Biosciences, Columbia University Mailman School of Public Health, New York, NY, USA.
²⁰ Merck Exploratory Science Center, Merck Research Laboratories, Cambridge, MA 02141, USA.
²¹ Department of Computer Science, Aberystwyth University, Aberystwyth, Ceredigion, SY23 3DB, United Kingdom; Human Development and Health, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
²² Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin, Turin, Italy.
²³ Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
²⁴ Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, QC, Canada; Department of Medicine, Universite de Sherbrooke, QC, Canada.
²⁵ The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands; Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands.
²⁶ Institute of Clinical Research, University of Southern Denmark, Odense, Denmark; Centre of Women's, Family and Child Health, University of South-Eastern Norway, Kongsberg, Norway.
²⁷ ISGlobal, Barcelona Institute for Global Health, Dr Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; PHAGEX Research Group, Blanquerna School of Health Science, Universitat Ramon Llull, Barcelona, Spain.
²⁸ Center for Human Health and the Environment, North Carolina State University, Raleigh, NC 27606, USA; Department of Biological Sciences, North Carolina State University, NC, USA.
²⁹ Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
³⁰ Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, Memphis, USA.
³¹ Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; Sachs' Children and Youth Hospital, Södersjukhuset, Stockholm, Sweden.
³² Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
³³ Department of Woman and Child Health, Ospedale Versilia, Azienda USL Toscana Nord Ovest, Viareggio, Italy.
³⁴ Department of Biochemistry and Functional Genomics, Université de Sherbrooke, QC, Canada; Department of Medical Biology, CIUSSS Saguenay-Lac-Saint-Jean, Chicoutimi Hospital, Saguenay, QC, Canada.
³⁵ Department of Public Health, Research Unit for Epidemiology, Aarhus University, 8000 Aarhus C, Denmark.
³⁶ Department of Child and Adolescent Psychiatry/ Psychology, Erasmus Medical Center, Sophia Children's Hospital, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands; Department of Social and Behavioral Science, Harvard TH Chan School of Public Health, 677 Huntington Ave, Boston, MA, USA.
³⁷ Bradford Institute of Health Research, Bradford Royal Infirmary, Bradford BD9 6RJ, UK.
³⁸ Department of Biological Sciences, North Carolina State University, NC, USA; Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27701, USA.
³⁹ Dept. Translational Research in Psychiatry, Max-Planck-Institute of Psychiatry, Munich, Germany.
⁴⁰ Division of Pediatric Pulmonology, Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, USA.
⁴¹ CHC, St Vincent, Liège-Rocourt, Belgium.
⁴² Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium.
⁴³ Univ. Grenoble Alpes, Inserm, CNRS, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, IAB, 38000 Grenoble, France.
⁴⁴ Dept. Translational Research in Psychiatry, Max-Planck-Institute of Psychiatry, Munich, Germany; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, USA.
⁴⁵ Department of Pediatrics, Ospedale dei Bambini Vittore Buzzi, University of Milan, Milan, Italy; Department of Health Sciences, University of Milan, Milan, Italy.
⁴⁶ Clinical Sciences, Heart Group, Murdoch Children's Research Institute, Melbourne, Australia; Department of Pediatrics, University of Melbourne, Melbourne, Australia; Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, UK.
⁴⁷ Grupo de Medicina Xenómica, Fundación Pública Galega de Merdicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), SERGAS, Santiago de Compostela, Spain; Centro de Investigación en Red de Enfermedades Raras (CIBERER) y Centro Nacional de Genotipado (CEGEN-PRB3), Universidad de Santiago de Compostela, Santiago de Compostela, Spain.
⁴⁸ Pediatric Nutrition and Human Development Research Unit, Universitat Rovira i Virgili, IISPV, Reus, Spain.
⁴⁹ Center for Environmental Research and Children's Health, School of Public Health, University of California, Berkeley, CA, USA.
⁵⁰ ISGlobal, Barcelona Institute for Global Health, Dr Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; IMIM (Hospital del Mar Medical Research Institute), Carrer del Dr. Aiguader 88, 08003 Barcelona, Spain.
⁵¹ Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium; Department Public Health & Primary care, Leuven University, Belgium.
⁵² Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway; Department of Pediatric Oncology and Hematology, Oslo University Hospital, Norway.
⁵³ Neonatal Department, Children's Memorial Health Institute, Warsaw, Poland.
⁵⁴ Department of Chronic Diseases and Ageing, Division of Mental and Physical Health, Norwegian Institute of Public Health, Oslo, Norway.
⁵⁵ Université de Paris, Centre for Research in Epidemiology and Statistics (CRESS), INSERM, INRAE, F-75004 Paris, France.
⁵⁶ Department of Medicine, Universite de Sherbrooke, QC, Canada; Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, MA, USA; Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
⁵⁷ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, BS8 2BN, UK; Department of Public Health, Section of Epidemiology, University of Copenhagen, Copenhagen, Denmark; The Novo Nordisk Foundation Center for Basic Metabolic Research, Section on Metabolic Genetics, Faculty of Medical and Health Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵⁸ Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27701, USA.
⁵⁹ Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, MA, USA.
⁶⁰ Human Development and Health, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
⁶¹ Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK; David Hide Asthma and Allergy Research Centre, Isle of Wight, UK.

PMID: 35690418
PMCID: PMC9623595
DOI: 10.1016/j.mrrev.2022.108415

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: Children; Cord blood; DNA methylation; EWAS; Sex.

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Figures

**Figure 1.**
Plot of meta-analysis EWAS results of differential methylation by sex in (a) newborns and (b) children. Sites with higher methylation in males compared to females are plotted above the x-axis while those with lower methylation in males compared to females are shown below the x-axis. The red lines represent the Bonferroni thresholds for significant CpG sites in each direction (higher and lower methylation in males compared to females) The grey boxes indicate the chromosome and the plot colors vary between blue and black for visual clarity between different chromosomes. The varying widths of the chromosomes corresponds to the length of the chromosomes

**Figure 2.**
Volcano plots of meta-analysis EWAS results of differential methylation by sex in (a) newborns and (b) children. Absolute effect sizes ranged from 0 to 0.23 (methylation β-value). Overall, there were more CpG sites with lower methylation in males compared to females.

**Figure 3.**
Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways with enrichment differences between males and females in (a) newborn and (b) older children. The size of the circles represents the number of differentially methylated genes in a pathway.

**Figure 4.**
Diseases with significant enrichment differences between males and females in (a) newborns and (b) older children. Disease enrichment analysis was performed using *DisGeNET*. The size of the circles represent the number of differentially methylated genes in a pathway.

See this image and copyright information in PMC

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[1] Roseboom T, de Rooij S, Painter R The dutch famine and its long-term consequences for adult health, Early Hum. Dev 82 (2006) 485–491. - PubMed

[2] Roseboom T, de Rooij S, Painter R The dutch famine and its long-term consequences for adult health, Early Hum. Dev 82 (2006) 485–491. - PubMed

[3] Barker DJ In utero programming of chronic disease, Clin. Sci 95 (1998) 115–128. - PubMed

[4] Barker DJ In utero programming of chronic disease, Clin. Sci 95 (1998) 115–128. - PubMed

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

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

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