DNA methylation at birth and lateral ventricular volume in childhood: a neuroimaging epigenetics study

Mannan Luo, Esther Walton, Alexander Neumann, Chris H.L. Thio, Janine F. Felix, Marinus H. van IJzendoorn, Irene Pappa, Charlotte A.M. Cecil*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Background: 

Lateral ventricular volume (LVV) enlargement has been repeatedly linked to schizophrenia; yet, what biological factors shape LVV during early development remain unclear. DNA methylation (DNAm), an essential process for neurodevelopment that is altered in schizophrenia, is a key molecular system of interest. 

Methods:

In this study, we conducted the first epigenome-wide association study of neonatal DNAm in cord blood with LVV in childhood (measured using T1-weighted brain scans at 10 years), based on data from a large population-based birth cohort, the Generation R Study (N = 840). Employing both probe-level and methylation profile score (MPS) approaches, we further examined whether epigenetic modifications identified at birth in cord blood are: (a) also observed cross-sectionally in childhood using peripheral blood DNAm at age of 10 years (Generation R, N = 370) and (b) prospectively associated with LVV measured in young adulthood in an all-male sample from the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 114). 

Results: 

At birth, DNAm levels at four CpGs (annotated to potassium channel tetramerization domain containing 3, KCTD3; SHH signaling and ciliogenesis regulator, SDCCAG8; glutaredoxin, GLRX) prospectively associated with childhood LVV after genome-wide correction; these genes have been implicated in brain development and psychiatric traits including schizophrenia. An MPS capturing a broader epigenetic profile of LVV – but not individual top hits – showed significant cross-sectional associations with LVV in childhood in Generation R and prospectively associated with LVV in early adulthood within ALSPAC. 

Conclusions: 

This study finds suggestive evidence that DNAm at birth prospectively associates with LVV at different life stages, albeit with small effect sizes. The prediction of MPS on LVV in a childhood sample and an independent male adult sample further underscores the stability and reproducibility of DNAm as a potential marker for LVV. Future studies with larger samples and comparable time points across development are needed to further elucidate how DNAm associates with this clinically relevant brain structure and risk for neuropsychiatric disorders, and what factors explain the identified DNAm profile of LVV at birth.

Original languageEnglish
Pages (from-to)77-90
Number of pages14
JournalJournal of Child Psychology and Psychiatry and Allied Disciplines
Volume65
Issue number1
Early online date19 Jul 2023
DOIs
Publication statusPublished - Jan 2024

Bibliographical note

Funding Information:
The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the School of Law and Faculty of Social Sciences at Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, the Rotterdam Homecare Foundation, and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR–MDC), Rotterdam. The authors gratefully acknowledge the contribution of children and parents, general practitioners, hospitals, midwives, and pharmacies in Rotterdam. The generation and management of the Illumina 450 K 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 Mr. Michael Verbiest, Ms. Mila Jhamai, Ms. Sarah Higgins, Mr. Marijn Verkerk, and Dr. Lisette Stolk for their help in creating the EWAS database. The authors thank Dr. A.Teumer for his work on the quality control and normalization scripts. The general design of the Generation R Study is made possible by financial support from Erasmus MC Rotterdam, Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development and the Ministry of Health, Welfare and Sport. The EWAS data were 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), funds from the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and a grant from the National Institute of Child and Human Development (R01HD068437). The authors 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. The UK Medical Research Council (MRC) and Wellcome Trust (217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant‐acknowledgements.pdf ). Analysis of ALSPAC data was funded by the UK Economic and Social Research Council (ESRC; ES/N000498/1). ARIES was funded by the Biotechnology and Biological Sciences Research Council (BBSRC; BBI025751/1 and BB/I025263/1). Supplementary funding to generate DNAm data which are (or will be) included in ARIES has been obtained from the MRC, ESRC, National Insitutes of Health, and other sources. ARIES is maintained under the auspices of the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/4 and MC_UU_00011/5). All the authors declare no conflict of interest. C.C. is supported by the European Union's Horizon 2020 Research and Innovation Programme (EarlyCause, grant agreement No 848158), the HorizonEurope Research and Innovation Programme (FAMILY, grant agreement No 101057529; HappyMums, grant agreement No 101057390) and the European Research Council (TEMPO; grant agreement No 101039672). M.L. was supported by the scholarship from the China Scholarship Council (201706990036). This work of M.L. was further supported by the Ter Meulen Grant of the Royal Netherlands Academy of Arts and Sciences (KNAW). E.W. was supported by the European Union Horizon 2020 and HorizonEurope research and innovation programme (EarlyCause, grant number 848158; BrainHealth UKRI guarantee EP/Y015037/1) and by CLOSER, whose mission is to maximize the use, value and impact of longitudinal studies. CLOSER was funded by the Economic and Social Research Council (ESRC) and the Medical Research Council (MRC) between 2012 and 2017. Its initial 5‐year grant was extended to March 2021 by the ESRC (grant reference: ES/K000357/1). The work of M.H.V.I.J. is supported by the Netherlands Organization for Scientific Research, Spinoza Award 2004. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and M.L. will serve as guarantor for the contents of this article.

Publisher Copyright:
© 2023 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.

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