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; 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; Ulrike Gehring

doi:10.1038/s41467-019-09671-3

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 HollowayTodd 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, Ulrike Gehring

Research output: Contribution to journal › Article › Academic › peer-review

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 (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.

Original language	English
Article number	1893
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-09671-3
Publication status	Published - 23 Apr 2019

Keywords

Adolescent
Adult
Birth Weight/genetics
Body Mass Index
Child
CpG Islands
DNA/genetics
DNA Methylation
Epigenesis, Genetic
Female
Fetal Development/genetics
Fetus
Folic Acid/blood
Genome, Human
Genome-Wide Association Study
Humans
Infant, Newborn
Male
Pregnancy
Prenatal Exposure Delayed Effects/blood
Smoking/adverse effects

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Küpers, L. K., Monnereau, C., Sharp, G. C., Yousefi, P., Salas, L. A., Ghantous, A., Page, C. M., Reese, S. E., Wilcox, A. J., Czamara, D., Starling, A. P., Novoloaca, A., Lent, S., Roy, R., Hoyo, C., Breton, C. V., Allard, C., Just, A. C., Bakulski, K. M., ... Gehring, U. (2019). Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight. Nature Communications, 10(1), Article 1893. https://doi.org/10.1038/s41467-019-09671-3

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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 (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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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, 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 & Gehring, U 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

TY - JOUR

T1 - Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight

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 - Gehring, Ulrike

PY - 2019/4/23

Y1 - 2019/4/23

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 (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.

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 (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.

KW - Adolescent

KW - Adult

KW - Birth Weight/genetics

KW - Body Mass Index

KW - Child

KW - CpG Islands

KW - DNA/genetics

KW - DNA Methylation

KW - Epigenesis, Genetic

KW - Female

KW - Fetal Development/genetics

KW - Fetus

KW - Folic Acid/blood

KW - Genome, Human

KW - Genome-Wide Association Study

KW - Humans

KW - Infant, Newborn

KW - Male

KW - Pregnancy

KW - Prenatal Exposure Delayed Effects/blood

KW - Smoking/adverse effects

U2 - 10.1038/s41467-019-09671-3

DO - 10.1038/s41467-019-09671-3

M3 - Article

C2 - 31015461

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1893

ER -

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

Abstract

Keywords

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