Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylati...

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Main Authors: Küpers, LK, Monnereau, C, Sharp, GC, Yousefi, P, Salas, LA, Ghantous, A, Page, CM, Reese, SE, Wilcox, AJ, Czamara, D, Starling, AP, Novoloaca, A, Lent, S, Roy, R, Hoyo, C, Breton, CV, Allard, C, Just, AC, Bakulski, KM, Holloway, JW, Everson, TM, Xu, C-J, Huang, R-C, DA Van Der Plaat, Wielscher, M, Merid, SK, Ullemar, V, Rezwan, FI, Lahti, J, Van Dongen, J, Langie, SAS, Richardson, TG, Magnus, MC, Nohr, EA, Xu, Z, Duijts, L, Zhao, S, Zhang, W, Plusquin, M, Demeo, DL, Solomon, O, Heimovaara, JH, Jima, DD, Gao, L, Bustamante, M, Perron, P, Wright, RO, Hertz-Picciotto, I, Zhang, H, Karagas, MR, Gehring, U, Marsit, CJ, Beilin, LJ, Vonk, JM, Jarvelin, M-R, Bergström, A, Örtqvist, AK, Ewart, S, Villa, PM, Moore, SE, Willemsen, G, Standaert, ARL, Håberg, SE, Sørensen, TIA, Taylor, JA, Räikkönen, K, Yang, IV, Kechris, K, Nawrot, TS, Silver, MJ, Gong, YY, Richiardi, L, Kogevinas, M, Litonjua, AA, Eskenazi, B, Huen, K, Mbarek, H, Maguire, RL, Dwyer, T, Vrijheid, M, Bouchard, L, Baccarelli, AA, Croen, LA, Karmaus, W, Anderson, D, De Vries, M, Sebert, S, Kere, J, Karlsson, R, Arshad, SH, Hämäläinen, E, Routledge, MN, Boomsma, DI, Feinberg, AP, Newschaffer, CJ, Govarts, E, Moisse, M, Fallin, MD, Melén, E, Prentice, AM, Kajantie, E, Almqvist, C, Oken, E, Dabelea, D, Boezen, HM, Melton, PE, Wright, RJ, Koppelman, GH, Trevisi, L, Hivert, M-F, Sunyer, J, Munthe-Kaas, MC, Murphy, SK, Corpeleijn, E, Wiemels, J, Holland, N, Herceg, Z, Binder, EB, Smith, G, Jaddoe, VWV, Lie, RT, Nystad, W, London, SJ, Lawlor, DA, Relton, CL, Snieder, H, Felix, JF
Format: Journal article
Language:English
Published: Springer Nature 2019
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author Küpers, LK
Monnereau, C
Sharp, GC
Yousefi, P
Salas, LA
Ghantous, A
Page, CM
Reese, SE
Wilcox, AJ
Czamara, D
Starling, AP
Novoloaca, A
Lent, S
Roy, R
Hoyo, C
Breton, CV
Allard, C
Just, AC
Bakulski, KM
Holloway, JW
Everson, TM
Xu, C-J
Huang, R-C
DA Van Der Plaat
Wielscher, M
Merid, SK
Ullemar, V
Rezwan, FI
Lahti, J
Van Dongen, J
Langie, SAS
Richardson, TG
Magnus, MC
Nohr, EA
Xu, Z
Duijts, L
Zhao, S
Zhang, W
Plusquin, M
Demeo, DL
Solomon, O
Heimovaara, JH
Jima, DD
Gao, L
Bustamante, M
Perron, P
Wright, RO
Hertz-Picciotto, I
Zhang, H
Karagas, MR
Gehring, U
Marsit, CJ
Beilin, LJ
Vonk, JM
Jarvelin, M-R
Bergström, A
Örtqvist, AK
Ewart, S
Villa, PM
Moore, SE
Willemsen, G
Standaert, ARL
Håberg, SE
Sørensen, TIA
Taylor, JA
Räikkönen, K
Yang, IV
Kechris, K
Nawrot, TS
Silver, MJ
Gong, YY
Richiardi, L
Kogevinas, M
Litonjua, AA
Eskenazi, B
Huen, K
Mbarek, H
Maguire, RL
Dwyer, T
Vrijheid, M
Bouchard, L
Baccarelli, AA
Croen, LA
Karmaus, W
Anderson, D
De Vries, M
Sebert, S
Kere, J
Karlsson, R
Arshad, SH
Hämäläinen, E
Routledge, MN
Boomsma, DI
Feinberg, AP
Newschaffer, CJ
Govarts, E
Moisse, M
Fallin, MD
Melén, E
Prentice, AM
Kajantie, E
Almqvist, C
Oken, E
Dabelea, D
Boezen, HM
Melton, PE
Wright, RJ
Koppelman, GH
Trevisi, L
Hivert, M-F
Sunyer, J
Munthe-Kaas, MC
Murphy, SK
Corpeleijn, E
Wiemels, J
Holland, N
Herceg, Z
Binder, EB
Smith, G
Jaddoe, VWV
Lie, RT
Nystad, W
London, SJ
Lawlor, DA
Relton, CL
Snieder, H
Felix, JF
author_facet Küpers, LK
Monnereau, C
Sharp, GC
Yousefi, P
Salas, LA
Ghantous, A
Page, CM
Reese, SE
Wilcox, AJ
Czamara, D
Starling, AP
Novoloaca, A
Lent, S
Roy, R
Hoyo, C
Breton, CV
Allard, C
Just, AC
Bakulski, KM
Holloway, JW
Everson, TM
Xu, C-J
Huang, R-C
DA Van Der Plaat
Wielscher, M
Merid, SK
Ullemar, V
Rezwan, FI
Lahti, J
Van Dongen, J
Langie, SAS
Richardson, TG
Magnus, MC
Nohr, EA
Xu, Z
Duijts, L
Zhao, S
Zhang, W
Plusquin, M
Demeo, DL
Solomon, O
Heimovaara, JH
Jima, DD
Gao, L
Bustamante, M
Perron, P
Wright, RO
Hertz-Picciotto, I
Zhang, H
Karagas, MR
Gehring, U
Marsit, CJ
Beilin, LJ
Vonk, JM
Jarvelin, M-R
Bergström, A
Örtqvist, AK
Ewart, S
Villa, PM
Moore, SE
Willemsen, G
Standaert, ARL
Håberg, SE
Sørensen, TIA
Taylor, JA
Räikkönen, K
Yang, IV
Kechris, K
Nawrot, TS
Silver, MJ
Gong, YY
Richiardi, L
Kogevinas, M
Litonjua, AA
Eskenazi, B
Huen, K
Mbarek, H
Maguire, RL
Dwyer, T
Vrijheid, M
Bouchard, L
Baccarelli, AA
Croen, LA
Karmaus, W
Anderson, D
De Vries, M
Sebert, S
Kere, J
Karlsson, R
Arshad, SH
Hämäläinen, E
Routledge, MN
Boomsma, DI
Feinberg, AP
Newschaffer, CJ
Govarts, E
Moisse, M
Fallin, MD
Melén, E
Prentice, AM
Kajantie, E
Almqvist, C
Oken, E
Dabelea, D
Boezen, HM
Melton, PE
Wright, RJ
Koppelman, GH
Trevisi, L
Hivert, M-F
Sunyer, J
Munthe-Kaas, MC
Murphy, SK
Corpeleijn, E
Wiemels, J
Holland, N
Herceg, Z
Binder, EB
Smith, G
Jaddoe, VWV
Lie, RT
Nystad, W
London, SJ
Lawlor, DA
Relton, CL
Snieder, H
Felix, JF
author_sort Küpers, LK
collection OXFORD
description Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10-74) and BMI in pregnancy (3/914, p = 1.13x10-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.
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spelling oxford-uuid:58a571a4-59c7-42f2-9365-5a71fa55d2592022-03-26T17:05:05ZMeta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweightJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:58a571a4-59c7-42f2-9365-5a71fa55d259EnglishSymplectic Elements at OxfordSpringer Nature2019Küpers, LKMonnereau, CSharp, GCYousefi, PSalas, LAGhantous, APage, CMReese, SEWilcox, AJCzamara, DStarling, APNovoloaca, ALent, SRoy, RHoyo, CBreton, CVAllard, CJust, ACBakulski, KMHolloway, JWEverson, TMXu, C-JHuang, R-CDA Van Der PlaatWielscher, MMerid, SKUllemar, VRezwan, FILahti, JVan Dongen, JLangie, SASRichardson, TGMagnus, MCNohr, EAXu, ZDuijts, LZhao, SZhang, WPlusquin, MDemeo, DLSolomon, OHeimovaara, JHJima, DDGao, LBustamante, MPerron, PWright, ROHertz-Picciotto, IZhang, HKaragas, MRGehring, UMarsit, CJBeilin, LJVonk, JMJarvelin, M-RBergström, AÖrtqvist, AKEwart, SVilla, PMMoore, SEWillemsen, GStandaert, ARLHåberg, SESørensen, TIATaylor, JARäikkönen, KYang, IVKechris, KNawrot, TSSilver, MJGong, YYRichiardi, LKogevinas, MLitonjua, AAEskenazi, BHuen, KMbarek, HMaguire, RLDwyer, TVrijheid, MBouchard, LBaccarelli, AACroen, LAKarmaus, WAnderson, DDe Vries, MSebert, SKere, JKarlsson, RArshad, SHHämäläinen, ERoutledge, MNBoomsma, DIFeinberg, APNewschaffer, CJGovarts, EMoisse, MFallin, MDMelén, EPrentice, AMKajantie, EAlmqvist, COken, EDabelea, DBoezen, HMMelton, PEWright, RJKoppelman, GHTrevisi, LHivert, M-FSunyer, JMunthe-Kaas, MCMurphy, SKCorpeleijn, EWiemels, JHolland, NHerceg, ZBinder, EBSmith, GJaddoe, VWVLie, RTNystad, WLondon, SJLawlor, DARelton, CLSnieder, HFelix, JFBirthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10-74) and BMI in pregnancy (3/914, p = 1.13x10-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.
spellingShingle Küpers, LK
Monnereau, C
Sharp, GC
Yousefi, P
Salas, LA
Ghantous, A
Page, CM
Reese, SE
Wilcox, AJ
Czamara, D
Starling, AP
Novoloaca, A
Lent, S
Roy, R
Hoyo, C
Breton, CV
Allard, C
Just, AC
Bakulski, KM
Holloway, JW
Everson, TM
Xu, C-J
Huang, R-C
DA Van Der Plaat
Wielscher, M
Merid, SK
Ullemar, V
Rezwan, FI
Lahti, J
Van Dongen, J
Langie, SAS
Richardson, TG
Magnus, MC
Nohr, EA
Xu, Z
Duijts, L
Zhao, S
Zhang, W
Plusquin, M
Demeo, DL
Solomon, O
Heimovaara, JH
Jima, DD
Gao, L
Bustamante, M
Perron, P
Wright, RO
Hertz-Picciotto, I
Zhang, H
Karagas, MR
Gehring, U
Marsit, CJ
Beilin, LJ
Vonk, JM
Jarvelin, M-R
Bergström, A
Örtqvist, AK
Ewart, S
Villa, PM
Moore, SE
Willemsen, G
Standaert, ARL
Håberg, SE
Sørensen, TIA
Taylor, JA
Räikkönen, K
Yang, IV
Kechris, K
Nawrot, TS
Silver, MJ
Gong, YY
Richiardi, L
Kogevinas, M
Litonjua, AA
Eskenazi, B
Huen, K
Mbarek, H
Maguire, RL
Dwyer, T
Vrijheid, M
Bouchard, L
Baccarelli, AA
Croen, LA
Karmaus, W
Anderson, D
De Vries, M
Sebert, S
Kere, J
Karlsson, R
Arshad, SH
Hämäläinen, E
Routledge, MN
Boomsma, DI
Feinberg, AP
Newschaffer, CJ
Govarts, E
Moisse, M
Fallin, MD
Melén, E
Prentice, AM
Kajantie, E
Almqvist, C
Oken, E
Dabelea, D
Boezen, HM
Melton, PE
Wright, RJ
Koppelman, GH
Trevisi, L
Hivert, M-F
Sunyer, J
Munthe-Kaas, MC
Murphy, SK
Corpeleijn, E
Wiemels, J
Holland, N
Herceg, Z
Binder, EB
Smith, G
Jaddoe, VWV
Lie, RT
Nystad, W
London, SJ
Lawlor, DA
Relton, CL
Snieder, H
Felix, JF
Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight
title Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight
title_full Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight
title_fullStr Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight
title_full_unstemmed Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight
title_short Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight
title_sort meta analysis of epigenome wide association studies in neonates reveals widespread differential dna methylation associated with birthweight
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AT devriesm metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT seberts metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT kerej metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT karlssonr metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT arshadsh metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT hamalainene metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT routledgemn metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT boomsmadi metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT feinbergap metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT newschaffercj metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT govartse metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT moissem metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT fallinmd metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT melene metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT prenticeam metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT kajantiee metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT almqvistc metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT okene metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT dabelead metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT boezenhm metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT meltonpe metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT wrightrj metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT koppelmangh metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT trevisil metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT hivertmf metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT sunyerj metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT munthekaasmc metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT murphysk metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT corpeleijne metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT wiemelsj metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT hollandn metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT hercegz metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT bindereb metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT smithg metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT jaddoevwv metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT liert metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT nystadw metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT londonsj metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT lawlorda metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT reltoncl metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT sniederh metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight
AT felixjf metaanalysisofepigenomewideassociationstudiesinneonatesrevealswidespreaddifferentialdnamethylationassociatedwithbirthweight