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Genome-wide DNA methylation patterns associated with general psychopathology in children

Research output: Contribution to journalArticlepeer-review

Jolien Rijlaarsdam, Edward D. Barker, Chiara Caserini, M. Elisabeth Koopman-Verhoeff, Rosa H. Mulder, Janine F. Felix, Charlotte A.M. Cecil

Original languageEnglish
Pages (from-to)214-220
Number of pages7
JournalJournal of psychiatric research
Volume140
DOIs
PublishedAug 2021

Bibliographical note

Funding Information: The Generation R Study is conducted by the Erasmus MC in close collaboration with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, Rotterdam, the Rotterdam Homecare Foundation, Rotterdam and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR-MDC), Rotterdam. We gratefully acknowledge the contribution of children and parents, general practitioners, hospitals, midwives, and pharmacies in Rotterdam. The generation and management of the Illumina 450K methylation array data (EWAS data) for the Generation R Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. The authors thank all colleagues involved in the generation and management of methylation data and genotyping. The general design of the Generation R Study is made possible by financial support from Erasmus MC, Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development, and the Ministry of Health, Welfare and Sport. The EWAS data was funded by a grant from the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA; project nr. 050-060-810), by funds from the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by a grant from the National Institute of Child and Human Development (R01HD068437). With regard to the ALSPAC data, we are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. With regard to the ALSPAC DNA methylation data, we thank all involved, particularly the laboratory scientists and bioinformaticians who contributed considerable time and expertise to the data generation and quality control. The UK Medical Research Council and the Wellcome Trust (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. ARIES was funded by the BBSRC (BBI025751/1 and BB/I025263/1). ARIES is maintained under the auspices of the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_12013/2 and MC_UU_12013/8). A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). This publication is the work of the authors who will serve as guarantors for the contents of this article. The work of JR was supported by the Netherlands Organization for Scientific Research (NWO ZonMw VENI, grant no 91618147). The work of CAMC has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sk?odowska-Curie grant agreement No 707404 and grant agreement No 848158 (EarlyCause Project). The work of EDB was supported by research awards from the National Institute of Child and Human Development (R01HD068437) and the Economic and Social Research Council (ES/R005516/1). The work of RHM was supported by grant agreement No 848158 (EarlyCause Project). This project received funding from the European Union's Horizon 2020 research and innovation programme (733206, LIFECYCLE; 824989, EUCAN-Connect). Funding Information: The Generation R Study is conducted by the Erasmus MC in close collaboration with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, Rotterdam, the Rotterdam Homecare Foundation, Rotterdam and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR-MDC), Rotterdam. We gratefully acknowledge the contribution of children and parents, general practitioners, hospitals, midwives, and pharmacies in Rotterdam. The generation and management of the Illumina 450K methylation array data (EWAS data) for the Generation R Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC , the Netherlands. The authors thank all colleagues involved in the generation and management of methylation data and genotyping. The general design of the Generation R Study is made possible by financial support from Erasmus MC , Erasmus University Rotterdam , the Netherlands Organization for Health Research and Development , and the Ministry of Health, Welfare and Sport . The EWAS data was funded by a grant from the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA; project nr. 050-060-810 ), by funds from the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC , and by a grant from the National Institute of Child and Human Development ( R01HD068437 ). Funding Information: This publication is the work of the authors who will serve as guarantors for the contents of this article. The work of JR was supported by the Netherlands Organization for Scientific Research (NWO ZonMw VENI, grant no 91618147 ). The work of CAMC has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 707404 and grant agreement No 848158 (EarlyCause Project). The work of EDB was supported by research awards from the National Institute of Child and Human Development ( R01HD068437 ) and the Economic and Social Research Council ( ES/R005516/1 ). The work of RHM was supported by grant agreement No 848158 (EarlyCause Project). This project received funding from the European Union's Horizon 2020 research and innovation programme ( 733206 , LIFECYCLE; 824989, EUCAN-Connect). Funding Information: With regard to the ALSPAC data, we are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. With regard to the ALSPAC DNA methylation data, we thank all involved, particularly the laboratory scientists and bioinformaticians who contributed considerable time and expertise to the data generation and quality control. The UK Medical Research Council and the Wellcome Trust (Grant ref: 217065/Z/19/Z ) and the University of Bristol provide core support for ALSPAC. ARIES was funded by the BBSRC ( BBI025751/1 and BB/I025263/1 ). ARIES is maintained under the auspices of the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_12013/2 and MC_UU_12013/8). A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). Publisher Copyright: © 2021 The Author(s) Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

Psychiatric symptoms are interrelated and found to be largely captured by a general psychopathology factor (GPF). Although epigenetic mechanisms, such as DNA methylation (DNAm), have been linked to individual psychiatric outcomes, associations with GPF remain unclear. Using data from 440 children aged 10 years participating in the Generation R Study, we examined the associations of DNAm with both general and specific (internalizing, externalizing) factors of psychopathology. Genome-wide DNAm levels, measured in peripheral blood using the Illumina 450K array, were clustered into wider co-methylation networks (‘modules’) using a weighted gene co-expression network analysis. One co-methylated module associated with GPF after multiple testing correction, while none associated with the specific factors. This module comprised of 218 CpG probes, of which 198 mapped onto different genes. The CpG most strongly driving the association with GPF was annotated to FZD1, a gene that has been implicated in schizophrenia and wider neurological processes. Associations between the probes contained in the co-methylated module and GPF were supported in an independent sample of children from the Avon Longitudinal Study of Parents and Children (ALSPAC), as evidenced by significant correlations in effect sizes. These findings might contribute to improving our understanding of dynamic molecular processes underlying complex psychiatric phenotypes.

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