Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation
2022
Solomon, Olivia | Huen, Karen | Yousefi, Paul | Küpers, Leanne | González, Juan | Suderman, Matthew | Reese, Sarah | Page, Christian | Gruzieva, Olena | Rzehak, Peter | Gao, Lu | Bakulski, Kelly | Novoloaca, Alexei | Allard, Catherine | Pappa, Irene | Llambrich, Maria | Vives, Marta | Jima, Dereje | Kvist, Tuomas | Baccarelli, Andrea | White, Cory | Rezwan, Faisal | Sharp, Gemma | Tindula, Gwen | Bergström, Anna | Grote, Veit | Dou, John | Isaevska, Elena | Magnus, Maria | Corpeleijn, Eva | Perron, Patrice | Jaddoe, Vincent W.V. | Nohr, Ellen | Maitre, Lea | Foraster, Maria | Hoyo, Cathrine | Håberg, Siri | Lahti, Jari | Demeo, Dawn | Zhang, Hongmei | Karmaus, Wilfried | Kull, Inger | Koletzko, Berthold | Feinberg, Jason | Gagliardi, Luigi | Bouchard, Luigi | Ramlau-Hansen, Cecilia Høst | Tiemeier, Henning | Santorelli, Gillian | Maguire, Rachel | Czamara, Darina | Litonjua, Augusto | Langhendries, Jean-Paul | Plusquin, Michelle | Lepeule, Johanna | Binder, Elisabeth | Verduci, Elvira | Dwyer, Terence | Carracedo, Ángel | Ferre, Natalia | Eskenazi, Brenda | Kogevinas, Manolis | Nawrot, Tim | Munthe-Kaas, Monica | Herceg, Zdenko | Relton, Caroline | Melén, Erik | Gruszfeld, Dariusz | Breton, Carrie | Fallin, M.D. | Ghantous, Akram | Nystad, Wenche | Heude, Barbara | Snieder, Harold | Hivert, Marie-France | Felix, Janine | Sørensen, Thorkild I.A. | Bustamante, Mariona | Murphy, Susan | Raikkönen, Katri | Oken, Emily | Holloway, John | Arshad, Syed Hasan | London, Stephanie | Holland, Nina | University of California [Berkeley] (UC Berkeley) ; University of California (UC) | University of Bristol [Bristol] | The Generation R Study Group ; Erasmus University Medical Center [Rotterdam] (Erasmus MC) | Erasmus University Medical Center [Rotterdam] (Erasmus MC) | National Institutes of Health [Bethesda] (NIH) | Norwegian Institute of Public Health [Oslo] (NIPH) | Oslo University Hospital [Oslo] | Dr von Hauner Children's Hospital [Munich, Germany] ; Ludwig-Maximilians-Universität München (LMU) | University of Michigan [Dearborn] ; University of Michigan System | Centre International de Recherche sur le Cancer ; Centre international de recherche sur le cancer | CHUS – Centre Hospitalier Universitaire de Sherbrooke [Sherbrooke, QC, Canada] | Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) ; Universitat de Barcelona (UB) | CIBER Epidemiologia y Salud Pùblica [Madrid, Spain] (CIBERESP) ; Instituto de Salud Carlos III [Madrid] (ISC) | North Carolina State University [Raleigh] (NC State) ; University of North Carolina System (UNC) | Helsingin yliopisto = Helsingfors universitet = University of Helsinki | Mailman School of Public Health Columbia University [New-York] | Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)) ; Conservatoire National des Arts et Métiers [CNAM] (CNAM) ; HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
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Show more [+] Less [-]English. OBJECTIVE Maternal glycemic dysregulation during pregnancy increases the risk of adverse health outcomes in her offspring, a risk thought to be linearly related to maternal hyperglycemia. It is hypothesized that changes in offspring DNA methylation (DNAm) underline these associations. RESEARCH DESIGN AND METHODS To address this hypothesis, we conducted fixed-effects meta-analyses of epigenome-wide association study (EWAS) results from eight birth cohorts investigating relationships between cord blood DNAm and fetal exposure to maternal glucose (Nmaximum = 3,503), insulin (Nmaximum = 2,062), and area under the curve of glucose (AUCgluc) following oral glucose tolerance tests (Nmaximum = 1,505). We performed lookup analyses for identified cytosine-guanine dinucleotides (CpGs) in independent observational cohorts to examine associations between DNAm and cardiometabolic traits as well as tissue-specific gene expression. RESULTS Greater maternal AUCgluc was associated with lower cord blood DNAm at neighboring CpGs cg26974062 (β [SE] −0.013 [2.1 × 10−3], P value corrected for false discovery rate [PFDR] = 5.1 × 10−3) and cg02988288 (β [SE]−0.013 [2.3 × 10−3], PFDR = 0.031) in TXNIP. These associations were attenuated in women with GDM. Lower blood DNAm at these two CpGs near TXNIP was associated with multiple metabolic traits later in life, including type 2 diabetes. TXNIP DNAm in liver biopsies was associated with hepatic expression of TXNIP. We observed little evidence of associations between either maternal glucose or insulin and cord blood DNAm. CONCLUSIONS Maternal hyperglycemia, as reflected by AUCgluc, was associated with lower cord blood DNAm at TXNIP. Associations between DNAm at these CpGs and metabolic traits in subsequent lookup analyses suggest that these may be candidate loci to investigate in future causal and mediation analyses.
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