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Merid, S.K., Novoloaca, A., Sharp, G.C. et al. Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age. Genome Med 12, 25 (2020). https://doi.org/10.1186/s13073-020-0716-9

Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age

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Author: Merid, Simon Kebede1,2; Novoloaca, Alexei3; Sharp, Gemma C.4,5;
Kupers, Leanne K.5,6,7; Kho, Alvin T.8,9; Roy, Ritu10,11; Gao, Lu12; Annesi-Maesano, Isabella13,14; Jain, Pooja15,16; Plusquin, Michelle15,17; Kogevinas, Manolis18,19,20,21; Allard, Catherine22; Vehmeijer, Florianne O.23,24; Kazmi, Nabila4,5; Salas, Lucas A.25; Rezwan, Faisal I.26; Zhang, Hongmei27; Sebert, Sylvain28,29,30; Czamara, Darina31; Rifas-Shiman, Sheryl L.32,33; Melton, Phillip E.34,35; Lawlor, Debbie A.4,5,36; Pershagen, Goran1,37; Breton, Carrie V.12; Huen, Karen38; Baiz, Nour13,14; Gagliardi, Luigi39; Nawrot, Tim S.15,40; Corpeleijn, Eva7; Perron, Patrice22,41; Duijts, Liesbeth23,24; Nohr, Ellen Aagaard42; Bustamante, Mariona18,19,20; Ewart, Susan L.43; Karmaus, Wilfried27; Zhao, Shanshan44; Page, Christian M.45; Herceg, Zdenko3; Jarvelin, Marjo-Riitta28,29,46,47; Lahti, Jari48,49; Baccarelli, Andrea A.50; Anderson, Denise51; Kachroo, Priyadarshini52,53; Relton, Caroline L.4,5,36; Bergstrom, Anna1,37; Eskenazi, Brenda54; Soomro, Munawar Hussain13,14; Vineis, Paolo55; Snieder, Harold7; Bouchard, Luigi22,56,57; Jaddoe, Vincent W.23,24; Sorensen, Thorkild I. A.4,58,59; Vrijheid, Martine18,19,20; Arshad, S. Hasan60,61; Holloway, John W.62; Haberg, Siri E.45; Magnus, Per45; Dwyer, Terence63,64; Binder, Elisabeth B.31,65; DeMeo, Dawn L.52,53; Vonk, Judith M.7,66; Newnham, John67; Tantisira, Kelan G.52,53; Kull, Inger2,68; Wiemels, Joseph L.69; Heude, Barbara70; Sunyer, Jordi18,19,20,21; Nystad, Wenche45; Munthe-Kaas, Monica C.45,71; Raikkonen, Katri45; Oken, Emily32,33; Huang, Rae-Chi51; Weiss, Scott T.52,53; Anto, Josep Maria18,19,20,21; Bousquet, Jean72,73; Kumar, Ashish1,74,75; Soderhall, Cilla76; Almqvist, Catarina77,78; Cardenas, Andres79; Gruzieva, Olena1,37; Xu, Cheng-Jian80; Reese, Sarah E.44; Kere, Juha81,82,83; Brodin, Petter76,84; Solomon, Olivia38; Wielscher, Matthias46; Holland, Nina38; Ghantous, Akram3; Hivert, Marie-France22,32,33,85; Felix, Janine F.23,24; Koppelman, Gerard H.80; London, Stephanie J.44; Melen, Erik1,2,86
Organizations: 1Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
2Karolinska Inst, Dept Clin Sci & Educ, Sodersjukhuset, Stockholm, Sweden.
3Int Agcy Res Canc, Epigenet Grp, Lyon, France.
4Univ Bristol, Integrat Epidemiol Unit, MRC, Bristol, Avon, England.
5Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol, Avon, England.
6Wageningen Univ & Res, Div Human Nutr & Hlth, Wageningen, Netherlands.
7Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands.
8Boston Childrens Hosp, Computat Hlth Informat Program, Boston, MA USA.
9Harvard Med Sch, Boston, MA 02115 USA.
10Univ Calif San Francisco, Computat Biol & Informat, San Francisco, CA 94143 USA.
11Univ Calif San Francisco, HDF Comprehens Canc Ctr, San Francisco, CA 94143 USA.
12Univ Southern Calif, Dept Prevent Med, Los Angeles, CA 90007 USA.
13Sorbonne Univ, Paris, France.
14INSERM, Epidemiol Allerg & Resp Dis Dept EPAR, Pierre Louis Inst Epidemiol & Publ Hlth, IPLESP UMRS 1136,St Antoine Med Sch, Paris, France.
15Imperial Coll London, Resp Infect & Immun, NIHR Hlth Protect Res Unit, London, England.
16Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.
17Hasselt Univ, Ctr Environm Sci, Hasselt, Belgium.
18Barcelona Inst Global Hlth, ISGlobal, Barcelona, Spain.
19UPF, Barcelona, Spain.
20CIBERESP, Madrid, Spain.
21IMIM Hosp del Mar Med Res Inst, Barcelona, Spain.
22CHU Sherbrooke, Ctr Rech, Sherbrooke, PQ, Canada.
23Erasmus MC, Univ Med Ctr Rotterdam, Generat R Study Grp, Rotterdam, Netherlands.
24Erasmus MC, Univ Med Ctr Rotterdam, Dept Pediat, Rotterdam, Netherlands.
25Dartmouth Coll, Geisel Sch Med, Dept Epidemiol, 1 Med Ctr Dr, Lebanon, NH 03756 USA.
26Cranfield Univ, Sch Water Energy & Environm, Cranfield MK43 0AL, Beds, England.
27Univ Memphis, Sch Publ Hlth, Div Epidemiol Biostat & Environm Hlth, Memphis, TN 38152 USA.
28Univ Oulu, Fac Med, Ctr Life Course Hlth Res, Oulu, Finland.
29Univ Oulu, Bioctr Oulu, Oulu, Finland.
30Imperial Coll London, Sch Publ Hlth, Dept Genom Complex Dis, London, England.
31Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany.
32Harvard Med Sch, Dept Populat Med, Div Chron Dis Res Lifecourse CoRAL, Boston, MA 02115 USA.
33Harvard Pilgrim Hlth Care Inst, Boston, MA USA.
34Curtin Univ, Sch Pharm & Biomed Sci, Fac Hlth Sci, Bentley, WA, Australia.
35Univ Western Australia, Sch Biomed Sci, Fac Hlth & Med Sci, Curtin UWA Ctr Genet Origins Hlth & Dis, Perth, WA, Australia.
36Bristol NIHR Biomed Res Ctr, Bristol, Avon, England.
37Ctr Occupat & Environm Med, Stockholm, Sweden.
38Univ Calif Berkeley, Childrens Environm Hlth Lab, Berkeley, CA 94720 USA.
39AUSL Toscana Nord Ovest, Osped Versilia, Div Neonatol & Pediat, Pisa, Italy.
40Leuven Univ, Dept Publ Hlth & Primary Care, Leuven, Belgium.
41Univ Sherbrooke, Dept Med, Sherbrooke, PQ, Canada.
42Univ Southern Denmark, Dept Clin Res, Res Unit Gynaecol & Obstet, Odense, Denmark.
43Michigan State Univ, Coll Vet Med, E Lansing, MI 48824 USA.
44NIEHS, Dept Hlth & Human Serv, NIH, Durham, NC USA.
45Norwegian Inst Publ Hlth, Oslo, Norway.
46Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London, England.
47Oulu Univ Hosp, Unit Primary Care, Oulu, Finland.
48Univ Helsinki, Fac Med, Dept Psychol & Logoped, Helsinki, Finland.
49Univ Turku, Turku Inst Adv Studies, Turku, Finland.
50Columbia Univ, Dept Environm Hlth Sci, Mailman Sch Publ Hlth, Med Ctr, New York, NY USA.
51Univ Western Australia, Telethon Kids Inst, Perth, WA, Australia.
52Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.
53Harvard Med Sch, Boston, MA USA.
54Univ Calif Berkeley, CERCH, Berkeley, CA 94720 USA.
55Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, London, England.
56Univ Sherbrooke, Dept Biochem, Sherbrooke, PQ, Canada.
57CIUSSS SI SJ, Dept Med Biol, Saguenay, PQ, Canada.
58Univ Copenhagen, Novo Nordisk Fdn, Ctr Basic Metab Res, Sect Metab Genet,Fac Hlth & Med Sci, Copenhagen, Denmark.
59Univ Copenhagen, Fac Hlth & Med Sci, Epidemiol Sect, Dept Publ Hlth, Copenhagen, Denmark.
60Univ Southampton, Fac Med, Clin & Expt Sci, Southampton, Hants, England.
61David Hide Asthma & Allergy Res Ctr, Newport, Wight, England.
62Univ Southampton, Fac Med, Human Dev & Hlth, Southampton, Hants, England.
63Univ Oxford, Nuffield Dept Womens & Reprod Hlth, Oxford, England.
64Univ Melbourne, Australia Fac Med Dent & Hlth Sci, Murdoch Childrens Res Inst, Melbourne, Vic, Australia.
65Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA USA.
66Univ Groningen, Univ Med Ctr Groningen, Groningen Res Inst Asthma & COPD GRIAC, Groningen, Netherlands.
67Univ Western Australia, UWA Med Sch, Fac Hlth & Med Sci, Perth, WA, Australia.
68Soder Sjukhuset, Sachs Childrens Hosp, S-11883 Stockholm, Sweden.
69Univ Southern Calif, Ctr Genet Epidemiol, Los Angeles, CA 90007 USA.
70Paris Descartes Univ, Res Team Early Life Origins Hlth EarOH, Sorbonne Paris Cite Ctr CRESS, UMR1153 Epidemiol & Biostat,INSERM, Paris, France.
71Oslo Univ Hosp, Dept Pediat Oncol & Hematol, Oslo, Norway.
72Univ Hosp, Montpellier, France.
73Charite, Dept Dermatol, Berlin, Germany.
74Univ Basel, Basel, Switzerland.
75Swiss Trop & Publ Hlth Inst, Basel, Switzerland.
76Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden.
77Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
78Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Pediat Allergy & Pulmonol Unit, Stockholm, Sweden.
79Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA.
80Univ Groningen, Univ Med Ctr Groningen, Dept Pediat Pulmonol & Pediat Allergol, Beatrix Childrens Hosp,GRIAC Res Inst Groningen, Groningen, Netherlands.
81Karolinska Inst, Dept Biosci & Nutr, Huddinge, Sweden.
82Folkhalsa Res Inst, Helsinki, Finland.
83Univ Helsinki, Stem Cells & Metab Res Program, Helsinki, Finland.
84Karolinska Univ Hosp, Dept Newborn Med, Stockholm, Sweden.
85Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA.
86South Gen Hosp, Sachs Childrens Hosp, Stockholm, Sweden.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.4 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2020120399344
Language: English
Published: Springer Nature, 2020
Publish Date: 2020-12-03
Description:

Abstract

Background: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children.

Methods: We performed meta-analysis of Illumina’s HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4–18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung.

Results: We identified 8899 CpGs in cord blood that were associated with gestational age (range 27–42 weeks), at Bonferroni significance, P < 1.06 × 10⁻⁷, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels.

Conclusions: We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.

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Series: Genome medicine
ISSN: 1756-994X
ISSN-E: 1756-994X
ISSN-L: 1756-994X
Volume: 12
Issue: 1
Article number: 25
DOI: 10.1186/s13073-020-0716-9
OADOI: https://oadoi.org/10.1186/s13073-020-0716-9
Type of Publication: A1 Journal article – refereed
Field of Science: 3123 Gynaecology and paediatrics
1184 Genetics, developmental biology, physiology
Subjects:
Development
Epigenetics
Gestational age
Preterm birth
Transcriptomics
Article
Funding: This study was specifically funded by a grant from the European Research Council (TRIBAL, grant agreement 757919). For all studies, detailed information can be found in Additional file 2: Supplementary information. Open access funding provided by Uppsala University.
Copyright information: © The Author(s). 2020. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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