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Gestational epigenetic age and ADHD symptoms in childhood: a prospective, multi-cohort study

Molecular Psychiatry (2024)Cite this article

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Abstract

Epigenetic age acceleration (EAA), defined as the difference between chronological age and epigenetically predicted age, was calculated from multiple gestational epigenetic clocks (Bohlin, EPIC overlap, and Knight) using DNA methylation levels from cord blood in three large population-based birth cohorts: the Generation R Study (The Netherlands), the Avon Longitudinal Study of Parents and Children (United Kingdom), and the Norwegian Mother, Father and Child Cohort Study (Norway). We hypothesized that a lower EAA associates prospectively with increased ADHD symptoms. We tested our hypotheses in these three cohorts and meta-analyzed the results (n = 3383). We replicated previous research on the association between gestational age (GA) and ADHD. Both clinically measured gestational age as well as epigenetic age measures at birth were negatively associated with ADHD symptoms at ages 5–7 years (clinical GA: β = −0.04, p < 0.001, Bohlin: β = −0.05, p = 0.01; EPIC overlap: β = −0.05, p = 0.01; Knight: β = −0.01, p = 0.26). Raw EAA (difference between clinical and epigenetically estimated gestational age) was positively associated with ADHD in our main model, whereas residual EAA (raw EAA corrected for clinical gestational age) was not associated with ADHD symptoms across cohorts. Overall, findings support a link between lower gestational age (either measured clinically or using epigenetic-derived estimates) and ADHD symptoms. Epigenetic age acceleration does not, however, add unique information about ADHD risk independent of clinically estimated gestational age at birth.

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Fig. 1: Forest plots of pooled analysis using the Bohlin clock.

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Acknowledgements

The Generation R Study is conducted by Erasmus MC, University Medical Center Rotterdam 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 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, and the Netherlands. We 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. We thank Dr. Alexander Teumer for his work on the quality control and normalization scripts. We are extremely grateful to all the families who took part in the ALSPAC 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 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 KS will serve as guarantors for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We are grateful to all the participating families in Norway who take part in this on-going cohort study. The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health, and the Norwegian Research Council/FUGE (grant no. 151918/S10). This work was partly supported by the Research Council of Norway through its Centers of Excellence funding scheme, project number 262700 and Grant Number 288083, 301004. The general design of the Generation R Study is made possible by financial support from the Erasmus MC, 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), 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). This project received funding from the European Union’s Horizon 2020 research and innovation programme (874739, LongITools; 824989, EUCAN-Connect) and from the European Joint Programming Initiative “A Healthy Diet for a Healthy Life” (JPI HDHL, NutriPROGRAM project, ZonMw the Netherlands no.529051022). CAMC and EW are supported by the European Union’s Horizon 2020 Research and Innovation Programme (EarlyCause, grant agreement No 848158); CAMC is also supported by the European Union’s 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). This research was conducted while CAMC was a Hevolution/AFAR New Investigator Awardee in Aging Biology and Geroscience Research. EW received funding from the National Institute of Mental Health of the National Institutes of Health (award number R01MH113930) and from CLOSER (ES/K000357/1) and from UK Research and Innovation (UKRI) under the UK government’s Horizon Europe / ERC Frontier Research Guarantee [BrainHealth, grant number EP/Y015037/1].

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Authors and Affiliations

  1. Department of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Centre, University Medical Center Rotterdam, Rotterdam, The Netherlands

    Kristina Salontaji, Henning Tiemeier & Charlotte A. M. Cecil

  2. The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    Kristina Salontaji & Janine F. Felix

  3. Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway

    Kristine L. Haftorn, Christian M. Page & Jon Bohlin

  4. Department of Psychology, University of Bath, Bath, United Kingdom

    Faye Sanders & Esther Walton

  5. Department of Physical Health and Ageing, Division of Mental and Physical Health, Norwegian Institute of Public Health, Oslo, Norway

    Christian M. Page

  6. Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    Janine F. Felix

  7. Promenta research centre, Department of Psychology, University of Oslo, Oslo, Norway

    Mona Bekkhus

  8. Department for methods development and analysis, section for modeling and bioinformatics, Division for infectious diseases, Norwegian Institute of Public Health, Oslo, Norway

    Jon Bohlin

  9. Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Medicine, Boston, MA, USA

    Henning Tiemeier

  10. Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    Charlotte A. M. Cecil

  11. Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands

    Charlotte A. M. Cecil

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  1. Kristina Salontaji
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Contributions

KS, HT and CAMC were responsible for conceptualization of this study. KS analyzed the data from the Generation R cohort and meta-analyzed the data. KLH and CMP analyzed the data from the MoBa cohort. FS and EW analyzed the data from the ALSPAC cohort. KS, HT and CAMC interpreted the data. KS wrote the original draft of the manuscript under the supervision of HT and CAMC, and comments were provided by JFF, EW, CMP, MB, and JB. All authors read and contributed to the preparation of the final manuscript. All authors read and approved the final manuscript.

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Correspondence to Charlotte A. M. Cecil.

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Salontaji, K., Haftorn, K.L., Sanders, F. et al. Gestational epigenetic age and ADHD symptoms in childhood: a prospective, multi-cohort study. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02544-2

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