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

Leanne K. Küpers, Claire Monnereau, Gemma C. Sharp, Paul Yousefi, Lucas A. Salas, Akram Ghantous, Christian M. Page, Sarah E. Reese, Allen J. Wilcox, Darina Czamara, Anne P. Starling, Alexei Novoloaca, Samantha Lent, Ritu Roy, Cathrine Hoyo, Carrie V. Breton, Catherine Allard, Allan C. Just, Kelly M. Bakulski, John W. Holloway & 107 others Todd M. Everson, Cheng Jian Xu, Rae Chi Huang, Diana A. van der Plaat, Matthias Wielscher, Simon Kebede Merid, Vilhelmina Ullemar, Faisal I. Rezwan, Jari Lahti, Jenny van Dongen, Sabine A.S. Langie, Tom G. Richardson, Maria C. Magnus, Ellen A. Nohr, Zongli Xu, Liesbeth Duijts, Shanshan Zhao, Weiming Zhang, Michelle Plusquin, Dawn L. DeMeo, Olivia Solomon, Joosje H. Heimovaara, Dereje D. Jima, Lu Gao, Mariona Bustamante, Patrice Perron, Robert O. Wright, Irva Hertz-Picciotto, Hongmei Zhang, Margaret R. Karagas, Ulrike Gehring, Carmen J. Marsit, Lawrence J. Beilin, Judith M. Vonk, Marjo Riitta Jarvelin, Anna Bergström, Anne K. Örtqvist, Susan Ewart, Pia M. Villa, Sophie E. Moore, Gonneke Willemsen, Arnout R.L. Standaert, Siri E. Håberg, Thorkild I.A. Sørensen, Jack A. Taylor, Katri Räikkönen, Ivana V. Yang, Katerina Kechris, Tim S. Nawrot, Matt J. Silver, Yun Yun Gong, Lorenzo Richiardi, Manolis Kogevinas, Augusto A. Litonjua, Brenda Eskenazi, Karen Huen, Hamdi Mbarek, Rachel L. Maguire, Terence Dwyer, Martine Vrijheid, Luigi Bouchard, Andrea A. Baccarelli, Lisa A. Croen, Wilfried Karmaus, Denise Anderson, Maaike de Vries, Sylvain Sebert, Juha Kere, Robert Karlsson, Syed Hasan Arshad, Esa Hämäläinen, Michael N. Routledge, Dorret I. Boomsma, Andrew P Feinberg, Craig J. Newschaffer, Eva Govarts, Matthieu Moisse, Daniele Daniele Fallin, Erik Melén, Andrew M. Prentice, Eero Kajantie, Catarina Almqvist, Emily Oken, Dana Dabelea, H. Marike Boezen, Phillip E. Melton, Rosalind J. Wright, Gerard H. Koppelman, Letizia Trevisi, Marie France Hivert, Jordi Sunyer, Monica C. Munthe-Kaas, Susan K. Murphy, Eva Corpeleijn, Joseph Wiemels, Nina Holland, Zdenko Herceg, Elisabeth B. Binder, George Davey Smith, Vincent W.V. Jaddoe, Rolv T. Lie, Wenche Nystad, Stephanie J. London, Debbie A. Lawlor, Caroline L. Relton, Harold Snieder, Janine F. Felix

Research output: Contribution to journalArticle

Abstract

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 (P Bonferroni < 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.

Original languageEnglish (US)
Article number1893
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

methylation
DNA Methylation
Meta-Analysis
Methylation
deoxyribonucleic acid
Association reactions
Newborn Infant
pregnancy
Pregnancy
Fetal Development
Folic Acid
Epigenomics
Causality
Blood
Smoking
Mothers
Health
Parturition
health
blood

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight. / Küpers, Leanne K.; Monnereau, Claire; Sharp, Gemma C.; Yousefi, Paul; Salas, Lucas A.; Ghantous, Akram; Page, Christian M.; Reese, Sarah E.; Wilcox, Allen J.; Czamara, Darina; Starling, Anne P.; Novoloaca, Alexei; Lent, Samantha; Roy, Ritu; Hoyo, Cathrine; Breton, Carrie V.; Allard, Catherine; Just, Allan C.; Bakulski, Kelly M.; Holloway, John W.; Everson, Todd M.; Xu, Cheng Jian; Huang, Rae Chi; van der Plaat, Diana A.; Wielscher, Matthias; Merid, Simon Kebede; Ullemar, Vilhelmina; Rezwan, Faisal I.; Lahti, Jari; van Dongen, Jenny; Langie, Sabine A.S.; Richardson, Tom G.; Magnus, Maria C.; Nohr, Ellen A.; Xu, Zongli; Duijts, Liesbeth; Zhao, Shanshan; Zhang, Weiming; Plusquin, Michelle; DeMeo, Dawn L.; Solomon, Olivia; Heimovaara, Joosje H.; Jima, Dereje D.; Gao, Lu; Bustamante, Mariona; Perron, Patrice; Wright, Robert O.; Hertz-Picciotto, Irva; Zhang, Hongmei; Karagas, Margaret R.; Gehring, Ulrike; Marsit, Carmen J.; Beilin, Lawrence J.; Vonk, Judith M.; Jarvelin, Marjo Riitta; Bergström, Anna; Örtqvist, Anne K.; Ewart, Susan; Villa, Pia M.; Moore, Sophie E.; Willemsen, Gonneke; Standaert, Arnout R.L.; Håberg, Siri E.; Sørensen, Thorkild I.A.; Taylor, Jack A.; Räikkönen, Katri; Yang, Ivana V.; Kechris, Katerina; Nawrot, Tim S.; Silver, Matt J.; Gong, Yun Yun; Richiardi, Lorenzo; Kogevinas, Manolis; Litonjua, Augusto A.; Eskenazi, Brenda; Huen, Karen; Mbarek, Hamdi; Maguire, Rachel L.; Dwyer, Terence; Vrijheid, Martine; Bouchard, Luigi; Baccarelli, Andrea A.; Croen, Lisa A.; Karmaus, Wilfried; Anderson, Denise; de Vries, Maaike; Sebert, Sylvain; Kere, Juha; Karlsson, Robert; Arshad, Syed Hasan; Hämäläinen, Esa; Routledge, Michael N.; Boomsma, Dorret I.; Feinberg, Andrew P; Newschaffer, Craig J.; Govarts, Eva; Moisse, Matthieu; Fallin, Daniele Daniele; Melén, Erik; Prentice, Andrew M.; Kajantie, Eero; Almqvist, Catarina; Oken, Emily; Dabelea, Dana; Boezen, H. Marike; Melton, Phillip E.; Wright, Rosalind J.; Koppelman, Gerard H.; Trevisi, Letizia; Hivert, Marie France; Sunyer, Jordi; Munthe-Kaas, Monica C.; Murphy, Susan K.; Corpeleijn, Eva; Wiemels, Joseph; Holland, Nina; Herceg, Zdenko; Binder, Elisabeth B.; Davey Smith, George; Jaddoe, Vincent W.V.; Lie, Rolv T.; Nystad, Wenche; London, Stephanie J.; Lawlor, Debbie A.; Relton, Caroline L.; Snieder, Harold; Felix, Janine F.

In: Nature communications, Vol. 10, No. 1, 1893, 01.12.2019.

Research output: Contribution to journalArticle

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, CJ, Huang, RC, van der Plaat, DA, 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, MR, 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, DD, Melén, E, Prentice, AM, Kajantie, E, Almqvist, C, Oken, E, Dabelea, D, Boezen, HM, Melton, PE, Wright, RJ, Koppelman, GH, Trevisi, L, Hivert, MF, Sunyer, J, Munthe-Kaas, MC, Murphy, SK, Corpeleijn, E, Wiemels, J, Holland, N, Herceg, Z, Binder, EB, Davey Smith, G, Jaddoe, VWV, Lie, RT, Nystad, W, London, SJ, Lawlor, DA, Relton, CL, Snieder, H & Felix, JF 2019, 'Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight', Nature communications, vol. 10, no. 1, 1893. https://doi.org/10.1038/s41467-019-09671-3
Küpers, Leanne K. ; Monnereau, Claire ; Sharp, Gemma C. ; Yousefi, Paul ; Salas, Lucas A. ; Ghantous, Akram ; Page, Christian M. ; Reese, Sarah E. ; Wilcox, Allen J. ; Czamara, Darina ; Starling, Anne P. ; Novoloaca, Alexei ; Lent, Samantha ; Roy, Ritu ; Hoyo, Cathrine ; Breton, Carrie V. ; Allard, Catherine ; Just, Allan C. ; Bakulski, Kelly M. ; Holloway, John W. ; Everson, Todd M. ; Xu, Cheng Jian ; Huang, Rae Chi ; van der Plaat, Diana A. ; Wielscher, Matthias ; Merid, Simon Kebede ; Ullemar, Vilhelmina ; Rezwan, Faisal I. ; Lahti, Jari ; van Dongen, Jenny ; Langie, Sabine A.S. ; Richardson, Tom G. ; Magnus, Maria C. ; Nohr, Ellen A. ; Xu, Zongli ; Duijts, Liesbeth ; Zhao, Shanshan ; Zhang, Weiming ; Plusquin, Michelle ; DeMeo, Dawn L. ; Solomon, Olivia ; Heimovaara, Joosje H. ; Jima, Dereje D. ; Gao, Lu ; Bustamante, Mariona ; Perron, Patrice ; Wright, Robert O. ; Hertz-Picciotto, Irva ; Zhang, Hongmei ; Karagas, Margaret R. ; Gehring, Ulrike ; Marsit, Carmen J. ; Beilin, Lawrence J. ; Vonk, Judith M. ; Jarvelin, Marjo Riitta ; Bergström, Anna ; Örtqvist, Anne K. ; Ewart, Susan ; Villa, Pia M. ; Moore, Sophie E. ; Willemsen, Gonneke ; Standaert, Arnout R.L. ; Håberg, Siri E. ; Sørensen, Thorkild I.A. ; Taylor, Jack A. ; Räikkönen, Katri ; Yang, Ivana V. ; Kechris, Katerina ; Nawrot, Tim S. ; Silver, Matt J. ; Gong, Yun Yun ; Richiardi, Lorenzo ; Kogevinas, Manolis ; Litonjua, Augusto A. ; Eskenazi, Brenda ; Huen, Karen ; Mbarek, Hamdi ; Maguire, Rachel L. ; Dwyer, Terence ; Vrijheid, Martine ; Bouchard, Luigi ; Baccarelli, Andrea A. ; Croen, Lisa A. ; Karmaus, Wilfried ; Anderson, Denise ; de Vries, Maaike ; Sebert, Sylvain ; Kere, Juha ; Karlsson, Robert ; Arshad, Syed Hasan ; Hämäläinen, Esa ; Routledge, Michael N. ; Boomsma, Dorret I. ; Feinberg, Andrew P ; Newschaffer, Craig J. ; Govarts, Eva ; Moisse, Matthieu ; Fallin, Daniele Daniele ; Melén, Erik ; Prentice, Andrew M. ; Kajantie, Eero ; Almqvist, Catarina ; Oken, Emily ; Dabelea, Dana ; Boezen, H. Marike ; Melton, Phillip E. ; Wright, Rosalind J. ; Koppelman, Gerard H. ; Trevisi, Letizia ; Hivert, Marie France ; Sunyer, Jordi ; Munthe-Kaas, Monica C. ; Murphy, Susan K. ; Corpeleijn, Eva ; Wiemels, Joseph ; Holland, Nina ; Herceg, Zdenko ; Binder, Elisabeth B. ; Davey Smith, George ; Jaddoe, Vincent W.V. ; Lie, Rolv T. ; Nystad, Wenche ; London, Stephanie J. ; Lawlor, Debbie A. ; Relton, Caroline L. ; Snieder, Harold ; Felix, Janine F. / Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight. In: Nature communications. 2019 ; Vol. 10, No. 1.
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abstract = "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 (P Bonferroni < 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.",
author = "K{\"u}pers, {Leanne K.} and Claire Monnereau and Sharp, {Gemma C.} and Paul Yousefi and Salas, {Lucas A.} and Akram Ghantous and Page, {Christian M.} and Reese, {Sarah E.} and Wilcox, {Allen J.} and Darina Czamara and Starling, {Anne P.} and Alexei Novoloaca and Samantha Lent and Ritu Roy and Cathrine Hoyo and Breton, {Carrie V.} and Catherine Allard and Just, {Allan C.} and Bakulski, {Kelly M.} and Holloway, {John W.} and Everson, {Todd M.} and Xu, {Cheng Jian} and Huang, {Rae Chi} and {van der Plaat}, {Diana A.} and Matthias Wielscher and Merid, {Simon Kebede} and Vilhelmina Ullemar and Rezwan, {Faisal I.} and Jari Lahti and {van Dongen}, Jenny and Langie, {Sabine A.S.} and Richardson, {Tom G.} and Magnus, {Maria C.} and Nohr, {Ellen A.} and Zongli Xu and Liesbeth Duijts and Shanshan Zhao and Weiming Zhang and Michelle Plusquin and DeMeo, {Dawn L.} and Olivia Solomon and Heimovaara, {Joosje H.} and Jima, {Dereje D.} and Lu Gao and Mariona Bustamante and Patrice Perron and Wright, {Robert O.} and Irva Hertz-Picciotto and Hongmei Zhang and Karagas, {Margaret R.} and Ulrike Gehring and Marsit, {Carmen J.} and Beilin, {Lawrence J.} and Vonk, {Judith M.} and Jarvelin, {Marjo Riitta} and Anna Bergstr{\"o}m and {\"O}rtqvist, {Anne K.} and Susan Ewart and Villa, {Pia M.} and Moore, {Sophie E.} and Gonneke Willemsen and Standaert, {Arnout R.L.} and H{\aa}berg, {Siri E.} and S{\o}rensen, {Thorkild I.A.} and Taylor, {Jack A.} and Katri R{\"a}ikk{\"o}nen and Yang, {Ivana V.} and Katerina Kechris and Nawrot, {Tim S.} and Silver, {Matt J.} and Gong, {Yun Yun} and Lorenzo Richiardi and Manolis Kogevinas and Litonjua, {Augusto A.} and Brenda Eskenazi and Karen Huen and Hamdi Mbarek and Maguire, {Rachel L.} and Terence Dwyer and Martine Vrijheid and Luigi Bouchard and Baccarelli, {Andrea A.} and Croen, {Lisa A.} and Wilfried Karmaus and Denise Anderson and {de Vries}, Maaike and Sylvain Sebert and Juha Kere and Robert Karlsson and Arshad, {Syed Hasan} and Esa H{\"a}m{\"a}l{\"a}inen and Routledge, {Michael N.} and Boomsma, {Dorret I.} and Feinberg, {Andrew P} and Newschaffer, {Craig J.} and Eva Govarts and Matthieu Moisse and Fallin, {Daniele Daniele} and Erik Mel{\'e}n and Prentice, {Andrew M.} and Eero Kajantie and Catarina Almqvist and Emily Oken and Dana Dabelea and Boezen, {H. Marike} and Melton, {Phillip E.} and Wright, {Rosalind J.} and Koppelman, {Gerard H.} and Letizia Trevisi and Hivert, {Marie France} and Jordi Sunyer and Munthe-Kaas, {Monica C.} and Murphy, {Susan K.} and Eva Corpeleijn and Joseph Wiemels and Nina Holland and Zdenko Herceg and Binder, {Elisabeth B.} and {Davey Smith}, George and Jaddoe, {Vincent W.V.} and Lie, {Rolv T.} and Wenche Nystad and London, {Stephanie J.} and Lawlor, {Debbie A.} and Relton, {Caroline L.} and Harold Snieder and Felix, {Janine F.}",
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AU - Küpers, Leanne K.

AU - Monnereau, Claire

AU - Sharp, Gemma C.

AU - Yousefi, Paul

AU - Salas, Lucas A.

AU - Ghantous, Akram

AU - Page, Christian M.

AU - Reese, Sarah E.

AU - Wilcox, Allen J.

AU - Czamara, Darina

AU - Starling, Anne P.

AU - Novoloaca, Alexei

AU - Lent, Samantha

AU - Roy, Ritu

AU - Hoyo, Cathrine

AU - Breton, Carrie V.

AU - Allard, Catherine

AU - Just, Allan C.

AU - Bakulski, Kelly M.

AU - Holloway, John W.

AU - Everson, Todd M.

AU - Xu, Cheng Jian

AU - Huang, Rae Chi

AU - van der Plaat, Diana A.

AU - Wielscher, Matthias

AU - Merid, Simon Kebede

AU - Ullemar, Vilhelmina

AU - Rezwan, Faisal I.

AU - Lahti, Jari

AU - van Dongen, Jenny

AU - Langie, Sabine A.S.

AU - Richardson, Tom G.

AU - Magnus, Maria C.

AU - Nohr, Ellen A.

AU - Xu, Zongli

AU - Duijts, Liesbeth

AU - Zhao, Shanshan

AU - Zhang, Weiming

AU - Plusquin, Michelle

AU - DeMeo, Dawn L.

AU - Solomon, Olivia

AU - Heimovaara, Joosje H.

AU - Jima, Dereje D.

AU - Gao, Lu

AU - Bustamante, Mariona

AU - Perron, Patrice

AU - Wright, Robert O.

AU - Hertz-Picciotto, Irva

AU - Zhang, Hongmei

AU - Karagas, Margaret R.

AU - Gehring, Ulrike

AU - Marsit, Carmen J.

AU - Beilin, Lawrence J.

AU - Vonk, Judith M.

AU - Jarvelin, Marjo Riitta

AU - Bergström, Anna

AU - Örtqvist, Anne K.

AU - Ewart, Susan

AU - Villa, Pia M.

AU - Moore, Sophie E.

AU - Willemsen, Gonneke

AU - Standaert, Arnout R.L.

AU - Håberg, Siri E.

AU - Sørensen, Thorkild I.A.

AU - Taylor, Jack A.

AU - Räikkönen, Katri

AU - Yang, Ivana V.

AU - Kechris, Katerina

AU - Nawrot, Tim S.

AU - Silver, Matt J.

AU - Gong, Yun Yun

AU - Richiardi, Lorenzo

AU - Kogevinas, Manolis

AU - Litonjua, Augusto A.

AU - Eskenazi, Brenda

AU - Huen, Karen

AU - Mbarek, Hamdi

AU - Maguire, Rachel L.

AU - Dwyer, Terence

AU - Vrijheid, Martine

AU - Bouchard, Luigi

AU - Baccarelli, Andrea A.

AU - Croen, Lisa A.

AU - Karmaus, Wilfried

AU - Anderson, Denise

AU - de Vries, Maaike

AU - Sebert, Sylvain

AU - Kere, Juha

AU - Karlsson, Robert

AU - Arshad, Syed Hasan

AU - Hämäläinen, Esa

AU - Routledge, Michael N.

AU - Boomsma, Dorret I.

AU - Feinberg, Andrew P

AU - Newschaffer, Craig J.

AU - Govarts, Eva

AU - Moisse, Matthieu

AU - Fallin, Daniele Daniele

AU - Melén, Erik

AU - Prentice, Andrew M.

AU - Kajantie, Eero

AU - Almqvist, Catarina

AU - Oken, Emily

AU - Dabelea, Dana

AU - Boezen, H. Marike

AU - Melton, Phillip E.

AU - Wright, Rosalind J.

AU - Koppelman, Gerard H.

AU - Trevisi, Letizia

AU - Hivert, Marie France

AU - Sunyer, Jordi

AU - Munthe-Kaas, Monica C.

AU - Murphy, Susan K.

AU - Corpeleijn, Eva

AU - Wiemels, Joseph

AU - Holland, Nina

AU - Herceg, Zdenko

AU - Binder, Elisabeth B.

AU - Davey Smith, George

AU - Jaddoe, Vincent W.V.

AU - Lie, Rolv T.

AU - Nystad, Wenche

AU - London, Stephanie J.

AU - Lawlor, Debbie A.

AU - Relton, Caroline L.

AU - Snieder, Harold

AU - Felix, Janine F.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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 (P Bonferroni < 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.

AB - 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 (P Bonferroni < 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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U2 - 10.1038/s41467-019-09671-3

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JO - Nature Communications

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