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

Darina Czamara, G. kçen Eraslan, Christian M. Page, Jari Lahti, Marius Lahti-Pulkkinen, Esa Hämäläinen, Eero Kajantie, Hannele Laivuori, Pia M. Villa, Rebecca M. Reynolds, Wenche Nystad, Siri E. Håberg, Stephanie J. London, Kieran J. O’Donnell, Elika Garg, Michael J. Meaney, Sonja Entringer, Pathik D. Wadhwa, Claudia Buss, Meaghan J. Jones & 25 others David T. S. Lin, Julie L. MacIsaac, Michael S. Kobor, Nastassja Koen, Heather J. Zar, Karestan C. Koenen, Shareefa Dalvie, Dan J. Stein, Ivan Kondofersky, Nikola S. Müller, Aartjan T. F. Beekman, Rick Jansen, Christel M. Middeldorp, Yuri Milaneschi, Wouter J. Peyrot, Robert Schoevers, Johannes H. Smit, E. J. C. de Geus, Brenda W. J. H. Penninx, Danielle Posthuma, Johannes H. Smit, Fabian J. Theis, Katri Räikkönen, E.B. Binder, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

Research output: Contribution to journalArticleAcademicpeer-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 languageEnglish
Article number2548
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019

Cite this

Czamara, D., Eraslan, G. K., Page, C. M., Lahti, J., Lahti-Pulkkinen, M., Hämäläinen, E., ... 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), [2548]. https://doi.org/10.1038/s41467-019-10461-0
Czamara, Darina ; Eraslan, G. kçen ; 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. ; MacIsaac, Julie L. ; Kobor, Michael S. ; Koen, Nastassja ; Zar, Heather J. ; Koenen, Karestan C. ; Dalvie, Shareefa ; Stein, Dan J. ; Kondofersky, Ivan ; Müller, Nikola S. ; Beekman, Aartjan T. F. ; Jansen, Rick ; Middeldorp, Christel M. ; Milaneschi, Yuri ; Peyrot, Wouter J. ; Schoevers, Robert ; Smit, Johannes H. ; de Geus, E. J. C. ; Penninx, Brenda W. J. H. ; Posthuma, Danielle ; Smit, Johannes H. ; Theis, Fabian J. ; Räikkönen, Katri ; Binder, E.B. ; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. / Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns. In: Nature Communications. 2019 ; Vol. 10, No. 1.
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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.",
author = "Darina Czamara and Eraslan, {G. k{\cc}en} and Page, {Christian M.} and Jari Lahti and Marius Lahti-Pulkkinen and Esa H{\"a}m{\"a}l{\"a}inen and Eero Kajantie and Hannele Laivuori and Villa, {Pia M.} and Reynolds, {Rebecca M.} and Wenche Nystad and H{\aa}berg, {Siri E.} and London, {Stephanie J.} and O’Donnell, {Kieran J.} and Elika Garg and Meaney, {Michael J.} and Sonja Entringer and Wadhwa, {Pathik D.} and Claudia Buss and Jones, {Meaghan J.} and Lin, {David T. S.} and MacIsaac, {Julie L.} and Kobor, {Michael S.} and Nastassja Koen and Zar, {Heather J.} and Koenen, {Karestan C.} and Shareefa Dalvie and Stein, {Dan J.} and Ivan Kondofersky and M{\"u}ller, {Nikola S.} and Beekman, {Aartjan T. F.} and Rick Jansen and Middeldorp, {Christel M.} and Yuri Milaneschi and Peyrot, {Wouter J.} and Robert Schoevers and Smit, {Johannes H.} and {de Geus}, {E. J. C.} and Penninx, {Brenda W. J. H.} and Danielle Posthuma and Smit, {Johannes H.} and Theis, {Fabian J.} and Katri R{\"a}ikk{\"o}nen and E.B. Binder and {Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium}",
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Czamara, D, Eraslan, GK, Page, CM, Lahti, J, Lahti-Pulkkinen, M, Hämäläinen, E, Kajantie, E, Laivuori, H, Villa, PM, Reynolds, RM, Nystad, W, Håberg, SE, London, SJ, O’Donnell, KJ, Garg, E, Meaney, MJ, Entringer, S, Wadhwa, PD, Buss, C, Jones, MJ, Lin, DTS, MacIsaac, JL, Kobor, MS, Koen, N, Zar, HJ, Koenen, KC, Dalvie, S, Stein, DJ, Kondofersky, I, Müller, NS, Beekman, ATF, Jansen, R, Middeldorp, CM, Milaneschi, Y, Peyrot, WJ, Schoevers, R, Smit, JH, de Geus, EJC, Penninx, BWJH, Posthuma, D, Smit, JH, Theis, FJ, Räikkönen, K, 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. https://doi.org/10.1038/s41467-019-10461-0

Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns. / Czamara, Darina; Eraslan, G. kçen; 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.; MacIsaac, Julie L.; Kobor, Michael S.; Koen, Nastassja; Zar, Heather J.; Koenen, Karestan C.; Dalvie, Shareefa; Stein, Dan J.; Kondofersky, Ivan; Müller, Nikola S.; Beekman, Aartjan T. F.; Jansen, Rick; Middeldorp, Christel M.; Milaneschi, Yuri; Peyrot, Wouter J.; Schoevers, Robert; Smit, Johannes H.; de Geus, E. J. C.; Penninx, Brenda W. J. H.; Posthuma, Danielle; Smit, Johannes H.; Theis, Fabian J.; Räikkönen, Katri; Binder, E.B.; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium.

In: Nature Communications, Vol. 10, No. 1, 2548, 01.12.2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

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

AU - Czamara, Darina

AU - Eraslan, G. kçen

AU - Page, Christian M.

AU - Lahti, Jari

AU - Lahti-Pulkkinen, Marius

AU - Hämäläinen, Esa

AU - Kajantie, Eero

AU - Laivuori, Hannele

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

AU - Meaney, Michael J.

AU - Entringer, Sonja

AU - Wadhwa, Pathik D.

AU - Buss, Claudia

AU - Jones, Meaghan J.

AU - Lin, David T. S.

AU - MacIsaac, Julie L.

AU - Kobor, Michael S.

AU - Koen, Nastassja

AU - Zar, Heather J.

AU - Koenen, Karestan C.

AU - Dalvie, Shareefa

AU - Stein, Dan J.

AU - Kondofersky, Ivan

AU - Müller, Nikola S.

AU - Beekman, Aartjan T. F.

AU - Jansen, Rick

AU - Middeldorp, Christel M.

AU - Milaneschi, Yuri

AU - Peyrot, Wouter J.

AU - Schoevers, Robert

AU - Smit, Johannes H.

AU - de Geus, E. J. C.

AU - Penninx, Brenda W. J. H.

AU - Posthuma, Danielle

AU - Smit, Johannes H.

AU - Theis, Fabian J.

AU - Räikkönen, Katri

AU - Binder, E.B.

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

PY - 2019/12/1

Y1 - 2019/12/1

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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Czamara D, Eraslan GK, Page CM, Lahti J, Lahti-Pulkkinen M, Hämäläinen E et al. Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns. Nature Communications. 2019 Dec 1;10(1). 2548. https://doi.org/10.1038/s41467-019-10461-0