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

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?-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.

SUBMITTER: Kupers LK

PROVIDER: S-EPMC6478731 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

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

Nature communications 20190423 1

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<sub>Bonferroni</sub> < 1.06 x 10<su ...[more]

PMID: 31015461

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Project description:BackgroundDNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits.MethodsWe examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment.ResultsDNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P < 1.06 × 10-7, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth Penrichment = 1; childhood Penrichment = 2.00 × 10-4; adolescence Penrichment = 2.10 × 10-7).ConclusionsThere were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity.

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

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

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