Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

Darina Czamara; Abdel Abdellaoui; Aartjan T.F. Beekman; Eske M. Derks; Conor V. Dolan; Jouke Jan Hottenga; Rick Jansen; Hamdi Mbarek; Christel M. Middeldorp; Yuri Milaneschi; Michel G. Nivard; Danielle Posthuma; Dorret I. Boomsma; Brenda W.J.H. Penninx; Elisabeth B. Binder; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

doi:10.1038/s41467-019-10461-0

Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

Darina Czamara, Abdel Abdellaoui, Aartjan T.F. Beekman, Eske M. Derks, Conor V. Dolan, Jouke Jan Hottenga, Rick Jansen, Hamdi Mbarek, Christel M. Middeldorp, Yuri Milaneschi, Michel G. Nivard, Danielle Posthuma, Dorret I. Boomsma, Brenda W.J.H. Penninx, Elisabeth B. Binder^*, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

^*Corresponding author for this work

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

Abstract

Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike's information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.

Original language	English
Article number	2548
Pages (from-to)	1-18
Number of pages	18
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-10461-0
Publication status	Published - 11 Jun 2019

Funding

We want to thank Susanne Sauer and Maik Ködel for their technical assistance and Jessica Keverne for language editing. We thank all mothers who took part in the on-going PREDO study. We are grateful to all the families in Norway who participate in the on-going MoBa cohort study. We thank the Drakenstein Child Health Study staff, and the clinical and administrative staff of the Western Cape Government Department of Health at Paarl Hospital and at the clinics for support of the Study. We also thank our collaborators and students. Finally, we thank all mothers and children enroled in the Dra-kenstein Child Health Study. We thank the research participants and employees of 23andMe, Inc. for their contribution to this study. This work was supported by the Academy of Finland (E.K., H.L., K.R., and J.L.); University of Helsinki Research Funds (J.L., M.L.P., and H.L.), British Heart Foundation (RMR); Tommy’s (RMR); European Commission (EK, KR, Horizon 2020 Award SC1–2016-RTD-733280 RECAP); NorFace DIAL (E.K., KR PremLife); Foundation for Pediatric Research (E.K.); Juho Vainio Foundation (E.K.); Novo Nordisk Foundation (E.K.); Signe and Ane Gyllenberg Foundation (E.K., K.R.); Sigrid Jusélius Foundation (E.K.); Finnish Medical Foundation (H.L.); Jane and Aatos Erkko Foundation (H.L.); Päivikki and Sakari Sohlberg Foundation (H.L., P.M.V.); the Clinical Graduate school in Pediatrics and Obstetrics/Gynaecology in University of Helsinki (P.M.V.). The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (contract no N01-ES-75558), NIH/NINDS (grant no.1 UO1 NS 047537–01 and grant no.2 UO1 NS 047537–06A1). For this work, MoBa 1 and 2 were supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019) and the Norwegian Research Council/ BIOBANK (grant no 221097). This work was also partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700. The Drakenstein Child Health Study is supported by the Bill and Melinda Gates Foundation (OPP 1017641); with additional support for this work from the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NICHD) under Award Number R21HD085849; and the Fogarty International Center (FIC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support for H.J.Z., D.J.S. and N.K., and for research reported in this publication was by the South African Medical Research Council (SAMRC); N.K. receives support from the SAMRC under a Self-Initiated Research Grant. The views and opinions expressed are those of the authors and do not necessarily represent the official views of the SAMRC. This work was also funded by the German Federal Ministry of Education and Research through the Research Consortium Integrated Network IntegraMent (grant 01ZX1314H) under the auspices of the e:Med Programme (NSM). The UCI cohort was supported by a European Research Area Network (ERA Net) Neuron grant (01EW1407A, CB) and National Institutes of Health grant (R01 HD-060628, CB) as well as NIH grant R01 MH-105538 (PDW). This work was also funded by the Canadian Institute for Advanced Research, Child and Brain Development Program, Toronto, ON, Canada (KJOD).

Funders	Funder number
NorFace DIAL
RMR
University of Helsinki Research Funds
National Institutes of Health
NIH Office of the Director	S10OD018164
Fogarty International Center
National Institute of Neurological Disorders and Stroke	2 UO1 NS 047537–06A1
National Institute of Environmental Health Sciences	N01-ES-75558, Z01-ES-49019
Bill and Melinda Gates Foundation	OPP 1017641
Canadian Institute for Advanced Research
Helsingin Yliopisto
Suomen Lääketieteen Säätiö
Eunice Kennedy Shriver National Institute of Child Health and Human Development	R21HD085849
British Heart Foundation
European Commission
South African Medical Research Council
Academy of Finland
Bundesministerium für Bildung und Forschung	01ZX1314H, R01 MH-105538, 01EW1407A, R01 HD-060628
Helse- og Omsorgsdepartementet
Jane ja Aatos Erkon Säätiö
Juho Vainion Säätiö
Päivikki ja Sakari Sohlbergin Säätiö
Signe ja Ane Gyllenbergin Säätiö
Norges forskningsråd	221097, 262700
Lastentautien Tutkimussäätiö
Sigrid Juséliuksen Säätiö
Horizon 2020	SC1–2016-RTD-733280 RECAP
Novo Nordisk Fonden

Cohort Studies

Netherlands Twin Register (NTR)

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Czamara, D., Abdellaoui, A., Beekman, A. T. F., Derks, E. M., Dolan, C. V., Hottenga, J. J., Jansen, R., Mbarek, H., Middeldorp, C. M., Milaneschi, Y., Nivard, M. G., Posthuma, D., Boomsma, D. I., Penninx, B. W. J. H., Binder, E. B., & Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (2019). Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns. Nature Communications, 10(1), 1-18. Article 2548. https://doi.org/10.1038/s41467-019-10461-0

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doi = "10.1038/s41467-019-10461-0",

language = "English",

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journal = "Nature Communications",

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Czamara, D, Abdellaoui, A, Beekman, ATF, Derks, EM, Dolan, CV , Hottenga, JJ , Jansen, R, Mbarek, H, Middeldorp, CM, Milaneschi, Y, Nivard, MG , Posthuma, D , Boomsma, DI, Penninx, BWJH, Binder, EB & Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium 2019, 'Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns', Nature Communications, vol. 10, no. 1, 2548, pp. 1-18. https://doi.org/10.1038/s41467-019-10461-0

TY - JOUR

T1 - Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

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AU - Page, Christian M.

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AU - Hämäläinen, Esa

AU - Kajantie, Eero

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AU - Villa, Pia M.

AU - Reynolds, Rebecca M.

AU - Nystad, Wenche

AU - Håberg, Siri E.

AU - London, Stephanie J.

AU - O’Donnell, Kieran J.

AU - Garg, Elika

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AU - Entringer, Sonja

AU - Wadhwa, Pathik D.

AU - Buss, Claudia

AU - Jones, Meaghan J.

AU - Lin, David T.S.

AU - MacIsaac, Julie L.

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AU - Koen, Nastassja

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AU - Koenen, Karestan C.

AU - Dalvie, Shareefa

AU - Stein, Dan J.

AU - Kondofersky, Ivan

AU - Müller, Nikola S.

AU - Theis, Fabian J.

AU - Wray, Naomi R.

AU - Ripke, Stephan

AU - Mattheisen, Manuel

AU - Trzaskowski, Maciej

AU - Byrne, Enda M.

AU - Abdellaoui, Abdel

AU - Adams, Mark J.

AU - Agerbo, Esben

AU - Air, Tracy M.

AU - Andlauer, Till F.M.

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AU - Bækvad-Hansen, Marie

AU - Beekman, Aartjan T.F.

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AU - Crawford, Gregory E.

AU - Davies, Gail

AU - Deary, Ian J.

AU - Degenhardt, Franziska

AU - Derks, Eske M.

AU - Direk, Nese

AU - Dolan, Conor V.

AU - Dunn, Erin C.

AU - Eley, Thalia C.

AU - Escott-Price, Valentina

AU - Kiadeh, Farnush Farhadi Hassan

AU - Finucane, Hilary K.

AU - Forstner, Andreas J.

AU - Frank, Josef

AU - Gaspar, Héléna A.

AU - Gill, Michael

AU - Goes, Fernando S.

AU - Gordon, Scott D.

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AU - Hall, Lynsey S.

AU - Hansen, Christine Søholm

AU - Hansen, Thomas F.

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AU - Hickie, Ian B.

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AU - Homuth, Georg

AU - Horn, Carsten

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AU - Jorgenson, Eric

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AU - Kohane, Isaac S.

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AU - Krogh, Jesper

AU - Kutalik, Zoltán

AU - Li, Yihan

AU - Lind, Penelope A.

AU - MacIntyre, Donald J.

AU - MacKinnon, Dean F.

AU - Maier, Robert M.

AU - Maier, Wolfgang

AU - Marchini, Jonathan

AU - Mbarek, Hamdi

AU - McGrath, Patrick

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AU - Medland, Sarah E.

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AU - Owen, Michael J.

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AU - Pedersen, Marianne Giørtz

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AU - Pettersson, Erik

AU - Peyrot, Wouter J.

AU - Pistis, Giorgio

AU - Posthuma, Danielle

AU - Quiroz, Jorge A.

AU - Qvist, Per

AU - Rice, John P.

AU - Riley, Brien P.

AU - Rivera, Margarita

AU - Mirza, Saira Saeed

AU - Schoevers, Robert

AU - Schulte, Eva C.

AU - Shen, Ling

AU - Shi, Jianxin

AU - Shyn, Stanley I.

AU - Sigurdsson, Engilbert

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AU - Smit, Johannes H.

AU - Smith, Daniel J.

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AU - Trubetskoy, Vassily

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AU - Domschke, Katharina

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AU - Kendler, Kenneth S.

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AU - Li, Qingqin S.

AU - Lucae, Susanne

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AU - Magnusson, Patrik K.

AU - Martin, Nicholas G.

AU - McIntosh, Andrew M.

AU - Metspalu, Andres

AU - Mors, Ole

AU - Mortensen, Preben Bo

AU - Müller-Myhsok, Bertram

AU - Nordentoft, Merete

AU - Nöthen, Markus M.

AU - O’Donovan, Michael C.

AU - Paciga, Sara A.

AU - Pedersen, Nancy L.

AU - Penninx, Brenda W.J.H.

AU - Perlis, Roy H.

AU - Porteous, David J.

AU - Potash, James B.

AU - Preisig, Martin

AU - Rietschel, Marcella

AU - Schaefer, Catherine

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AU - Smoller, Jordan W.

AU - Stefansson, Kari

AU - Tiemeier, Henning

AU - Uher, Rudolf

AU - Völzke, Henry

AU - Weissman, Myrna M.

AU - Werge, Thomas

AU - Lewis, Cathryn M.

AU - Levinson, Douglas F.

AU - Breen, Gerome

AU - Børglum, Anders D.

AU - Sullivan, Patrick F.

AU - Räikkönen, Katri

AU - Binder, Elisabeth B.

AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

PY - 2019/6/11

Y1 - 2019/6/11

N2 - Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike's information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.

AB - Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike's information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.

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UR - http://www.scopus.com/inward/citedby.url?scp=85067229888&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-10461-0

DO - 10.1038/s41467-019-10461-0

M3 - Article

C2 - 31186427

SN - 2041-1723

VL - 10

SP - 1

EP - 18

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2548

ER -

Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

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Cohort Studies

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