Abstract

Neurodevelopmental disorders (NDD) are characterized by impairments in brain development that affect motor and cognitive systems. Early identification of NDD risk factors is crucial for prevention. Metabolomic profiling holds promise for early detection but remains underexplored in longitudinal studies. Here, we map the longitudinal metabolomic profiles in 3212 samples covering 683 metabolites from 581 mother-child pairs at six timepoints in the Danish COPSAC2010 cohort to assess childhood NDD risk over a 10-years follow-up period. Cross-validated sPLS models identify metabolic biomarkers and patterns associated with NDD, with maternal gestational week 24 metabolic profile showing the best prediction. Metabolite trajectories prior 18-month of age are linked to NDD risk. Quinolinate is consistently associated with NDD across timepoints and mediated the effect of maternal inflammation on NDD. In the single metabolite analysis, no metabolites remained significant after multiple testing correction. In this work, we provide valuable insights into the role of the longitudinal metabolome in neurodevelopment.

Data availability

Source data are provided with this paper. Participant-level personally identifiable data are protected under the Danish data protection act and European Regulation 2016/679 of the European Parliament and of the Council (GDPR) that prohibit distribution even in pseudo-anonymized form. However, participant-level data can be made available under a data transfer agreement as part of a collaboration effort with COPSAC (chawes@copsac.com). Source data are provided with this paper.

Code availability

The custom code employed in this research is freely accessible to the public for transparency and reproducibility purposes. Related codes can be found at https:// github already.https://github.com/tiwa1125/Longitudinal_metabolome and Zenodo (https://doi.org/10.5281/zenodo.17340755).

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Acknowledgements

We thank the children and families of the COPSAC2010 cohort study for all their support and commitment. We acknowledge and appreciate the efforts of the COPSAC research team. All funding received by COPSAC is listed on www.copsac.com. T.W., M.A., and B.C. are supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 946228). The COPSYCH study was funded by The Lundbeck Foundation (grant no R269-2017-5), and The Capital Region Research Foundation has provided core support to the COPSAC research Center.

Author information

Author notes

These authors jointly supervised this work: Bjørn H. Ebdrup, Bo Chawes.

Authors and Affiliations

COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital-Herlev and Gentofte, Copenhagen, Denmark

Tingting Wang, Rebecca Vinding, Nicklas Brustad, Liang Chen, María Hernández-Lorca, Mina Ali, Julie Bøjstrup Rosenberg, Parisa Mohammadzadeh, Michael Widdowson, Parvaneh Ebrahimi, Morten A. Rasmussen, Jonathan Thorsen, Klaus Bønnelykke & Bo Chawes 1.

Mental Health Centre Glostrup, Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS) & Center for Neuropsychiatric Schizophrenia Research (CNSR), University of Copenhagen, Glostrup, Denmark

Jens Richardt Møllegaard Jepsen, María Hernández-Lorca, Julie Bøjstrup Rosenberg, Parisa Mohammadzadeh & Bjørn H. Ebdrup 1.

Mental Health Centre for Child and Adolescent Psychiatry-Research unit, Mental Health Services in the Capital Region of Denmark, Copenhagen, Denmark

Jens Richardt Møllegaard Jepsen 1.

Department of Food Science, Section of Food Microbiology, Gut health and Fermentation, University of Copenhagen, Copenhagen, Denmark

Parvaneh Ebrahimi & Morten A. Rasmussen 1.

Department of Health Technology, Section of Bioinformatics, Technical University of Denmark, Lyngby, Denmark

Parvaneh Ebrahimi 1.

Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

Jonathan Thorsen, Klaus Bønnelykke, Bjørn H. Ebdrup & Bo Chawes

Authors

1. Tingting Wang
2. Jens Richardt Møllegaard Jepsen
3. Rebecca Vinding
4. Nicklas Brustad
5. Liang Chen
6. María Hernández-Lorca
7. Mina Ali
8. Julie Bøjstrup Rosenberg
9. Parisa Mohammadzadeh
10. Michael Widdowson
11. Parvaneh Ebrahimi
12. Morten A. Rasmussen
13. Jonathan Thorsen
14. Klaus Bønnelykke
15. Bjørn H. Ebdrup
16. Bo Chawes

Contributions

T.W. performed all analyses and has written the first draft of the manuscript, under supervision from B.E. and B.C. T.W. and B.C. formulated the research question, concept and design. P.M. and J.B.R. were the primary clinical investigators in the COPSYCH 10-year follow-up visit and substantial contributors to the data collection. J.R.M., R.V., N.B., L.C., M.H., M.A., J.B.R., P.M., M.W., P.E., M.A.R., J.T., K.B., B.H., and B.C. rigorously reviewed and revised the manuscript, providing substantial intellectual input and contributing to the analysis plan and interpretation of results. Approval of the final manuscript, ensuring its accuracy and integrity, was unanimous among all authors. The corresponding author had full access to the data and had final responsibility for the decision to submit for publication. No honorarium, grant, or other form of payment was given to any of the authors to produce this manuscript.

Corresponding authors

Correspondence to Tingting Wang or Bo Chawes.

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Competing interests

B.H.E. is part of the Advisory Board of Boehringer Ingelheim, Lundbeck Pharma A/S; and has received lecture fees from Boehringer Ingelheim, Otsuka Pharma Scandinavia AB, and Lundbeck Pharma A/S. J.T. has received a lecture fee from AstraZeneca. The remaining authors declare no conflicts of interest, whether potential, perceived, or actual, pertaining to the content of this manuscript.

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