Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns
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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.
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In a study of over 2000 newborns, GxE and G+E models outperformed models with G or E only in predicting DNA methylation at DMRs, indicating a synergistic interaction between genetic and environmental factors.
“The GxE and G+E models outperformed the models with G or E only in predicting DNAm at the DMRs, indicating a synergistic interaction between genetic and environmental factors.”
From Epigenetics and depression (2019) · cites this paper as [68]
The Discussion (page unavailable) says GxE interactions and G + E additive effects best explained most variable methylation sites, ahead of genotype alone; Table 1 lists cohorts totaling 2,365 newborns. But the paper analyzes variably methylated regions (VMRs), not DMRs, and distinguishes additive G + E effects from interactions. The claim’s characterization of both models as evidence of a synergistic interaction is therefore not supported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredBoth G+E and GxE models were enriched for DMRs associated with GWAS of psychiatric disease, including MDD.
“Notably, both models (G+E and GxE) were enriched for DMRs associated with GWAS of psychiatric disease, including MDD. 68”
From Epigenetics and depression (2019) · cites this paper as [68]
The Results (Disease relevance; page unavailable) report GWAS enrichment for functional SNPs in GxE and G+E models and include major depressive disorder (MDD) among the GWAS examined. They do not report enrichment of DMRs, or establish that both models were enriched specifically for MDD; the highlighted psychiatric enrichments are for autism and ADHD. (LLM, conf=0.86)
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- Authors
- Czamara, D., Eraslan, G., Page, C. M., Lahti, J., Lahti-Pulkkinen, M., Hämäläinen, E., Kajantie, E., Laivuori, H., Villa, P. M., Reynolds, R. M., Nystad, W., Håberg, S. E., London, S. J., O’Donnell, K. J., Garg, E., Meaney, M. J., Entringer, S., Wadhwa, P. D., Buss, C., Jones, M. J., Lin, D. T. S., MacIsaac, J. L., Kobor, M. S., Koen, N., Zar, H. J., Koenen, K. C., Dalvie, S., Stein, D. J., Kondofersky, I., Müller, N. S., Theis, F. J., Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Wray, N. R., Ripke, S., Mattheisen, M., Trzaskowski, M., Byrne, E. M., Abdellaoui, A., Adams, M. J., Agerbo, E., Air, T. M., Andlauer, T. F. M., Bacanu, S.-A., Bækvad-Hansen, M., Beekman, A. T. F., Bigdeli, T. B., Blackwood, D. H. R., Bryois, J., Buttenschøn, H. N., Bybjerg-Grauholm, J., Cai, N., Castelao, E., Christensen, J. H., Clarke, T.-K., Coleman, J. R. I., Colodro-Conde, L., Couvy-Duchesne, B., Craddock, N., Crawford, G. E., Davies, G., Deary, I. J., Degenhardt, F., Derks, E. M., Direk, N., Dolan, C. V., Dunn, E. C., Eley, T. C., Escott-Price, V., Kiadeh, F. F. H., Finucane, H. K., Forstner, A. J., Frank, J., Gaspar, H. A., Gill, M., Goes, F. S., Gordon, S. D., Grove, J., Hall, L. S., Hansen, C. S., Hansen, T. F., Herms, S., Hickie, I. B., Hoffmann, P., Homuth, G., Horn, C., Hottenga, J.-J., Hougaard, D. M., Ising, M., Jansen, R., Jorgenson, E., Knowles, J. A., Kohane, I. S., Kraft, J., Kretzschmar, W. W., Krogh, J., Kutalik, Z., Li, Y., Lind, P. A., MacIntyre, D. J., MacKinnon, D. F., Maier, R. M., Maier, W., Marchini, J., Mbarek, H., McGrath, P., McGuffin, P., Medland, S. E., Mehta, D., Middeldorp, C. M., Mihailov, E., Milaneschi, Y., Milani, L., Mondimore, F. M., Montgomery, G. W., Mostafavi, S., Mullins, N., Nauck, M., Ng, B., Nivard, M. G., Nyholt, D. R., O’Reilly, P. F., Oskarsson, H., Owen, M. J., Painter, J. N., Pedersen, C. B., Pedersen, M. G., Peterson, R. E., Pettersson, E., Peyrot, W. J., Pistis, G., Posthuma, D., Quiroz, J. A., Qvist, P., Rice, J. P., Riley, B. P., Rivera, M., Mirza, S. S., Schoevers, R., Schulte, E. C., Shen, L., Shi, J., Shyn, S. I., Sigurdsson, E., Sinnamon, G. C. B., Smit, J. H., Smith, D. J., Stefansson, H., Steinberg, S., Streit, F., Strohmaier, J., Tansey, K. E., Teismann, H., Teumer, A., Thompson, W., Thomson, P. A., Thorgeirsson, T. E., Traylor, M., Treutlein, J., Trubetskoy, V., Uitterlinden, A. G., Umbricht, D., Van der Auwera, S., van Hemert, A. M., Viktorin, A., Visscher, P. M., Wang, Y., Webb, B. T., Weinsheimer, S. M., Wellmann, J., Willemsen, G., Witt, S. H., Wu, Y., Xi, H. S., Yang, J., Zhang, F., Arolt, V., Baune, B. T., Berger, K., Boomsma, D. I., Cichon, S., Dannlowski, U., de Geus, E. J. C., DePaulo, J. R., Domenici, E., Domschke, K., Esko, T., Grabe, H. J., Hamilton, S. P., Hayward, C., Heath, A. C., Kendler, K. S., Kloiber, S., Lewis, G., Li, Q. S., Lucae, S., Madden, P. A. F., Magnusson, P. K., Martin, N. G., McIntosh, A. M., Metspalu, A., Mors, O., Mortensen, P. B., Müller-Myhsok, B., Nordentoft, M., Nöthen, M. M., O’Donovan, M. C., Paciga, S. A., Pedersen, N. L., Penninx, B. W. J. H., Perlis, R. H., Porteous, D. J., Potash, J. B., Preisig, M., Rietschel, M., Schaefer, C., Schulze, T. G., Smoller, J. W., Stefansson, K., Tiemeier, H., Uher, R., Völzke, H., Weissman, M. M., Werge, T., Lewis, C. M., Levinson, D. F., Breen, G., Børglum, A. D., Sullivan, P. F., Räikkönen, K., & Binder, E. B.
- Affiliations
- Max Planck Institute of Psychiatry (DE)
- Helmholtz Munich (DE)
- Oslo University Hospital (NO)
- University of Helsinki (FI)
- British Heart Foundation Centre for Cardiovascular Science (GB)
- Norwegian Institute of Public Health (NO)
- National Institutes of Health (US)
- Douglas Mental Health University Institute (CA)
- University of California, Irvine (US)
- University of British Columbia (CA)
- South African Medical Research Council (ZA)
- Harvard University (US)
- University of Cape Town (ZA)
- The University of Queensland (AU)
- Broad Institute (US)
- Aarhus University (DK)
- Amsterdam Public Health (NL)
- University of Edinburgh (GB)
- The University of Adelaide (AU)
- Munich Cluster for Systems Neurology (DE)
- Virginia Commonwealth University (US)
- GGZ inGeest (NL)
- Karolinska Institutet (SE)
- European Bioinformatics Institute (GB)
- Centre Hospitalier Universitaire Vaudois (CH)
- King's College London (GB)
- Cardiff University (GB)
- Duke University (US)
- University of Bonn (DE)
- QIMR Berghofer Medical Research Institute (AU)
- Heidelberg University (DE)
- Trinity College Dublin (IE)
- Johns Hopkins University (US)
- Newcastle University (GB)
- Statens Serum Institut (DK)
- Mental Health Services (DK)
- The University of Sydney (AU)
- Universität Greifswald (DE)
- F. Hoffmann-La Roche AG (CH)
- Kaiser Permanente (US)
- University of Southern California (US)
- Brigham and Women's Hospital (US)
- Charité – Universitätsmedizin Berlin (DE)
- Centre for Human Genetics (GB)
- University of Copenhagen (DK)
- SIB Swiss Institute of Bioinformatics (CH)
- University of Oxford (GB)
- Columbia University Irving Medical Center (US)
- Queensland University of Technology (AU)
- University of Tartu (EE)
- Universitätsmedizin Greifswald (DE)
- Washington University in St. Louis (US)
- Universidad de Granada (ES)
- Erasmus MC (NL)
- University Medical Center Groningen (NL)
- Institut für Psychiatrische Phänomik und Genomik (DE)
- National Cancer Institute (US)
- James Cook University (AU)
- deCODE Genetics (Iceland) (IS)
- University of Münster (DE)
- University of California San Diego (US)
- University of Cambridge (GB)
- Pfizer (United States) (US)
- University of Trento (IT)
- University of Freiburg (DE)
- Kaiser Permanente Northern California (US)
- Institute of Genetics and Cancer (GB)
- Centre for Addiction and Mental Health (CA)
- University College London (GB)
- Janssen Research & Development (United States) (US)
- Aarhus University Hospital (DK)
- Copenhagen University Hospital (DK)
- University of Iowa (US)
- Dalhousie University (CA)
- Stanford University (US)
- University of North Carolina at Chapel Hill (US)
- Emory University (US)
- Corresponding author
- Binder, Elisabeth B.
- ORCID
- Czamara, Darina
- Eraslan, Gökçen
- Page, Christian M.
- Lahti, Jari
- Lahti-Pulkkinen, Marius
- Hämäläinen, Esa
- Kajantie, Eero
- Laivuori, Hannele
- Villa, Pia M.
- Reynolds, Rebecca M.
- Nystad, Wenche
- Håberg, Siri E.
- London, Stephanie J.
- O’Donnell, Kieran J.
- Garg, Elika
- Meaney, Michael J.
- Entringer, Sonja
- Wadhwa, Pathik D.
- Buss, Claudia
- Jones, Meaghan J.
- Lin, David T. S.
- Kobor, Michael S.
- Koen, Nastassja
- Zar, Heather J.
- Koenen, Karestan C.
- Dalvie, Shareefa
- Stein, Dan J.
- Müller, Nikola S.
- Theis, Fabian J.
- Wray, Naomi R.
- Ripke, Stephan
- Mattheisen, Manuel
- Trzaskowski, Maciej
- Byrne, Enda M.
- Abdellaoui, Abdel
- Adams, Mark J.
- Agerbo, Esben
- Air, Tracy M.
- Andlauer, Till F. M.
- Bacanu, Silviu-Alin
- Beekman, Aartjan T. F.
- Bigdeli, Tim B.
- Blackwood, Douglas H. R.
- Bryois, Julien
- Buttenschøn, Henriette N.
- Cai, Na
- Castelao, Enrique
- Christensen, Jane Hvarregaard
- Clarke, Toni-Kim
- Coleman, Jonathan R. I.
- Craddock, Nick
- Crawford, Gregory E.
- Davies, Gail
- Deary, Ian J.
- Degenhardt, Franziska
- Derks, Eske M.
- Dolan, Conor V.
- Dunn, Erin C.
- Eley, Thalia C.
- Finucane, Hilary K.
- Forstner, Andreas J.
- Frank, Josef
- Gaspar, Héléna A.
- Gill, Michael
- Goes, Fernando S.
- Gordon, Scott D.
- Grove, Jakob
- Hall, Lynsey S.
- Hansen, Christine Søholm
- Hansen, Thomas F.
- Herms, Stefan
- Hickie, Ian B.
- Hoffmann, Per
- Homuth, Georg
- Hottenga, Jouke-Jan
- Hougaard, David M.
- Jorgenson, Eric
- Knowles, James A.
- Kohane, Isaac S.
- Kraft, Julia
- Kretzschmar, Warren W.
- Krogh, Jesper
- Kutalik, Zoltán
- Li, Yihan
- Lind, Penelope A.
- MacIntyre, Donald J.
- MacKinnon, Dean F.
- Marchini, Jonathan
- Mbarek, Hamdi
- McGrath, Patrick
- Medland, Sarah E.
- Mehta, Divya
- Middeldorp, Christel M.
- Milaneschi, Yuri
- Milani, Lili
- Mondimore, Francis M.
- Montgomery, Grant W.
- Mostafavi, Sara
- Mullins, Niamh
- Nauck, Matthias
- Ng, Bernard
- Nivard, Michel G.
- Nyholt, Dale R.
- O’Reilly, Paul F.
- Owen, Michael J.
- Painter, Jodie N.
- Pedersen, Carsten Bøcker
- Peterson, Roseann E.
- Pettersson, Erik
- Peyrot, Wouter J.
- Pistis, Giorgio
- Quiroz, Jorge A.
- Qvist, Per
- Rice, John P.
- Riley, Brien P.
- Rivera, Margarita
- Mirza, Saira Saeed
- Schoevers, Robert
- Schulte, Eva C.
- Shi, Jianxin
- Shyn, Stanley I.
- Sinnamon, Grant C. B.
- Smit, Johannes H.
- Steinberg, Stacy
- Streit, Fabian
- Strohmaier, Jana
- Tansey, Katherine E.
- Teismann, Henning
- Teumer, Alexander
- Thomson, Pippa A.
- Thorgeirsson, Thorgeir E.
- Traylor, Matthew
- Treutlein, Jens
- Trubetskoy, Vassily
- Uitterlinden, André G.
- Umbricht, Daniel
- Viktorin, Alexander
- Visscher, Peter M.
- Wang, Yunpeng
- Webb, Bradley T.
- Weinsheimer, Shantel Marie
- Wellmann, Jürgen
- Willemsen, Gonneke
- Witt, Stephanie H.
- Wu, Yang
- Xi, Hualin S.
- Yang, Jian
- Zhang, Futao
- Arolt, Volker
- Baune, Bernhard T.
- Boomsma, Dorret I.
- Cichon, Sven
- Dannlowski, Udo
- DePaulo, J. Raymond
- Domenici, Enrico
- Domschke, Katharina
- Esko, Tõnu
- Grabe, Hans J.
- Hamilton, Steven P.
- Hayward, Caroline
- Heath, Andrew C.
- Kendler, Kenneth S.
- Kloiber, Stefan
- Lewis, Glyn
- Li, Qingqin S.
- Lucae, Susanne
- Madden, Pamela A. F.
- Magnusson, Patrik K.
- Martin, Nicholas G.
- McIntosh, Andrew M.
- Metspalu, Andres
- Mors, Ole
- Mortensen, Preben Bo
- Nordentoft, Merete
- Nöthen, Markus M.
- O’Donovan, Michael C.
- Paciga, Sara A.
- Pedersen, Nancy L.
- Penninx, Brenda W. J. H.
- Perlis, Roy H.
- Porteous, David J.
- Potash, James B.
- Preisig, Martin
- Rietschel, Marcella
- Schulze, Thomas G.
- Smoller, Jordan W.
- Tiemeier, Henning
- Uher, Rudolf
- Völzke, Henry
- Weissman, Myrna M.
- Werge, Thomas
- Lewis, Cathryn M.
- Levinson, Douglas F.
- Breen, Gerome
- Børglum, Anders D.
- Sullivan, Patrick F.
- Räikkönen, Katri
- Binder, Elisabeth B.
- Venue
- Nature Communications
- Published
- 2019-06-11
- Volume
- 10
- Issue
- 1
- Pages
- 2548-2548
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6559955
- OpenAlex
- W2950541136
- Cited by
- 143
- References
- 94
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 21 · 2023: 14 · 2022: 27 · 2021: 29 · 2020: 22 · 2019: 5
- FWCI
- 6.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by)
- VU Research Portal (publishedVersion, other-oa)
- SERVAL (Université de Lausanne) (publishedVersion, cc-by)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- QUT ePrints (Queensland University of Technology) (submittedVersion, cc-by)
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- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- WOS
- Funders
- Bill and Melinda Gates Foundation (OPP1017641, 1017641)
- Emory University
- Helsingin Yliopisto
- Suomen Lääketieteen Säätiö
- Wellcome Trust (104036/Z/14/Z)
- British Heart Foundation (262700)
- European Commission (733280, 221097, HORIZON2020, 32,33, 132,133, 64,65, 39,40)
- South African Medical Research Council
- Academy of Finland
- Bundesministerium für Bildung und Forschung (01EW1407A)
- Helse- og Omsorgsdepartementet (N01-ES-75558, UO1 NS 047537-01, UO1 NS 047537-06A1)
- Jane ja Aatos Erkon Säätiö
- Juho Vainion Säätiö
- Novo Nordisk
- Päivikki ja Sakari Sohlbergin Säätiö
- Signe ja Ane Gyllenbergin Säätiö
- Norges Forskningsråd (262700., 221097)
- Technische Universität München (85748)
- Lastentautien Tutkimussäätiö
- Sigrid Juséliuksen Säätiö
- University of Cape Town
- Tommy's
- Novo Nordisk Fonden (NNF18OC0034448)
- National Institutes of Health (262700, n01es75558-11-0-1, 1s10od018164-01, 39,40, N01-ES-75558)
- School of Medicine, Emory University
- Medical Research Council (MR/L023784/2, MR/K026992/1, MR/L010305/1, 262700, MC_UU_00007/10)
- National Institute of Mental Health (U01MH109536, R01MH105538)
- Fogarty International Center
- National Institute of Neurological Disorders and Stroke (1-UO1-NS-047537, UO1-NS-047537, 2UO1 NS047537-06A1, 047537-01, UO1 NS 047537–01, NS 047537, U01NS047537, 047537-06A1, UO1 NS 047537-06A1, NS 047537-06A1, 1 UO1 NS 047537‐01)
- National Institute of Environmental Health Sciences (ES-75558, N01-ES, UO1 NS 047537-01, N01ES75558, N01 ES075558, 1 UO1 NS 047537-01, no.2 UO1 NS 047537–06A1, Z01ES049019, 2 UO1 NS 047537-06A1, Z01ES49019)
- National Institute of Child Health and Human Development
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD085849, R01HD060628, HD-060628)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- DNA methylation, umbilical cord blood, neonates, prenatal environmental factors, genotypes, gene-environment interaction, epigenetics, Akaike information criterion, CpG sites, genetic variants, disease risk
- MeSH terms
- DNA, Female, Fetal Blood, Genotype, Humans, Infant, Newborn, Male, Pregnancy, Risk Factors, Cohort Studies, DNA Methylation, Epigenesis, Genetic, Gene-Environment Interaction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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