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Variably methylated regions in the newborn epigenome: environmental, genetic and combined influences

View ORCID ProfileDarina Czamara, Gökçen Eraslan, Jari Lahti, Christian M. Page, 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, David TS 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, Fabian J Theis, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Katri Räikkönen, Elisabeth B Binder*
doi: https://doi.org/10.1101/436113
Darina Czamara
1Max-Planck-Institute of Psychiatry, Department of Translational Research in Psychiatry, Munich, Germany
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  • ORCID record for Darina Czamara
Gökçen Eraslan
2Institute of Computational Biology, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
3School of Life Sciences, Weihenstephan, Technische Universität München, Freising, Germany
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Jari Lahti
4Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Finland
5Helsinki Collegium for Advanced Studies, University of Helsinki, Finland
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Christian M. Page
6Oslo Centre for Biostatistics and Epidemiology, Research Support Unit, Oslo University Hospital, Oslo, Norway
7Center for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
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Marius Lahti-Pulkkinen
4Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Finland
8British Heart Foundation Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, UK
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Esa Hämäläinen
9HUSLAB and Department of Clinical Chemistry, Helsinki University, Helsinki, Finland
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Eero Kajantie
10Oulu University Hospital and University of Oulu, PEDEGO Research Unit, MRC Oulu, Finland
11Hospital for Children and Adolescents, University of Helsinki and Helsinki University Hospital, Finland
12National Institute for Health and Welfare, Helsinki, Finland
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Hannele Laivuori
13Medical and Clinical Genetics and Obstetrics and Gynaecology University of Helsinki and Helsinki University Central Hospital, Finland
14Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Finland
15Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
16Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland
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Pia M Villa
13Medical and Clinical Genetics and Obstetrics and Gynaecology University of Helsinki and Helsinki University Central Hospital, Finland
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Rebecca M. Reynolds
8British Heart Foundation Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, UK
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Wenche Nystad
17Department of Chronic Diseases and Ageing, Norwegian Institute of Public Health, Oslo, Norway
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Siri E Håberg
7Center for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
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Stephanie J London
18Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, U.S. Department of Health and Human Services, Research Triangle Park, North Carolina, United States of America
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Kieran J O’Donnell
19Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada
20Sackler Program for Epigenetics and Psychobiology at McGill University, Montreal, QC, Canada
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Elika Garg
19Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada
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Michael J Meaney
19Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada
20Sackler Program for Epigenetics and Psychobiology at McGill University, Montreal, QC, Canada
21Singapore Institute for Clinical Sciences, Singapore
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Sonja Entringer
22Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Institute of Medical Psychology, Berlin, Germany
23University of California, Irvine, Development, Health, and Disease Research Program, Orange, CA, USA
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Pathik D Wadhwa
23University of California, Irvine, Development, Health, and Disease Research Program, Orange, CA, USA
24Departments of Psychiatry and Human Behavior, Obstetrics and Gynecology, and Epidemiology, University of California, Irvine, School of Medicine, Irvine, CA, USA
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Claudia Buss
22Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Institute of Medical Psychology, Berlin, Germany
23University of California, Irvine, Development, Health, and Disease Research Program, Orange, CA, USA
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Meaghan J Jones
25Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia and the BC Children’s Hospital Research Institute, Vancouver, BC, Canada
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David TS Lin
25Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia and the BC Children’s Hospital Research Institute, Vancouver, BC, Canada
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Julie L MacIsaac
25Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia and the BC Children’s Hospital Research Institute, Vancouver, BC, Canada
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Michael S Kobor
25Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia and the BC Children’s Hospital Research Institute, Vancouver, BC, Canada
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Nastassja Koen
26Department of Psychiatry and Mental Health, University of Cape Town, South Africa
27South African Medical Research Council (SAMRC), Unit on Risk and Resilience in Mental Disorders, Cape Town, South Africa
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Heather J Zar
28Department of Paediatrics & Child Health and SAMRC Unit on Child and Adolescent Health, University of Cape Town, South Africa
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Karestan C Koenen
29Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA
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Shareefa Dalvie
26Department of Psychiatry and Mental Health, University of Cape Town, South Africa
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Dan J Stein
26Department of Psychiatry and Mental Health, University of Cape Town, South Africa
27South African Medical Research Council (SAMRC), Unit on Risk and Resilience in Mental Disorders, Cape Town, South Africa
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Ivan Kondofersky
2Institute of Computational Biology, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
30Department of Mathematics, Technische Universität München, Munich, Germany
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Nikola S Müller
2Institute of Computational Biology, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
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Fabian J Theis
2Institute of Computational Biology, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
30Department of Mathematics, Technische Universität München, Munich, Germany
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Katri Räikkönen
4Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Finland
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Elisabeth B Binder*
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Abstract

Background 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. We examined the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs), defined as consecutive CpGs showing the highest variability of DNAm in 4 independent cohorts (PREDO, DCHS, UCI, MoBa, N=2,934).

Results We used Akaike’s information criterion to test which factors best explained variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E) including maternal demographic, psychosocial and metabolism related phenotypes, genotypes in cis (G), or their additive (G+E) or interaction (GxE) effects. G+E and GxE models consistently best explained variability in DNAm of VMRs across the cohorts, with G explaining the remaining sites best. VMRs best explained by G, GxE or G+E, as well as their associated functional genetic variants (predicted using deep learning algorithms), were located in distinct genomic regions, with different enrichments for transcription and enhancer marks. Genetic variants of not only G and G+E models, but also of variants in GxE models were significantly enriched in genome wide association studies (GWAS) for complex disorders.

Conclusion Genetic and environmental factors in combination best explain DNAm at VMRs. The CpGs best explained by G, G+E or GxE are functionally distinct. The enrichment of GxE variants in GWAS for complex disorders supports their importance for disease risk.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Variably methylated regions in the newborn epigenome: environmental, genetic and combined influences
Darina Czamara, Gökçen Eraslan, Jari Lahti, Christian M. Page, 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, David TS 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, Fabian J Theis, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Katri Räikkönen, Elisabeth B Binder*
bioRxiv 436113; doi: https://doi.org/10.1101/436113
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Variably methylated regions in the newborn epigenome: environmental, genetic and combined influences
Darina Czamara, Gökçen Eraslan, Jari Lahti, Christian M. Page, 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, David TS 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, Fabian J Theis, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Katri Räikkönen, Elisabeth B Binder*
bioRxiv 436113; doi: https://doi.org/10.1101/436113

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