Early childhood serum and urine metabolite signatures of internalizing, externalizing, and ADHD traits and their trajectories to adolescence: the Rhea mother-child cohort.
13 affiliations
- 1Department of Hygiene, Social-Preventive Medicine & Medical Statistics, Medical School, Aristotle University of Thessaloniki, University Campus, Thessaloniki, Greece.
- 2Department of Psychology, School of Social Sciences, University of Crete, Rethymno, Crete, Greece.
- 3Faculty of Medicine, Clinic of Preventive Medicine and Nutrition, University of Crete, Heraklion, Greece.
- 4Nutrition and Metabolism Branch, International Agency for Research On Cancer (IARC-WHO), Lyon, France.
- 5Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK.
- 6Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
- 7Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain.
- 8Barcelona Institute for Global Health, Barcelona, Spain.
- 9Universitat Pompeu Fabra, Barcelona, Spain.
- 10Department of Surgery & Cancer, Faculty of Medicine, Imperial College London, London, UK.
- 11The Department of Paediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands. [email protected].
- 12Department of Nutrition and Dietetics Sciences, School of Health Sciences, Hellenic Mediterranean University, Sitia, Crete, Greece.
- 13Clinical and Epidemiological Neuroscience (NeuroÈpia), Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain.
Abstract
Introduction
Early-life emotional and behavioral difficulties increase vulnerability to later psychopathology, but it remains unclear whether a biological footprint is detectable in early childhood.Objectives
We aimed to identify serum- and urine-based metabolite signatures of internalizing, externalizing, and attention-deficit/hyperactivity disorder (ADHD) traits in 6-year-old children and examine their associations with traits through adolescence.Methods
We analyzed 196 participants of the Rhea cohort (Greece), with serum and urine metabolomics at age 6 and internalizing, externalizing, and ADHD traits assessed at ages 6, 11, and 15. Trait- and biofluid-specific metabolite signatures were identified using elastic net regression with cross-validation. Associations with subsequent traits at repeated time points were evaluated using confounder-adjusted linear mixed-effects models.Results
Metabolite signatures comprising amino acids, acylcarnitines, phosphatidylcholines, and gut microbiota-related metabolites were identified for internalizing, externalizing, and ADHD traits. Serum metabolite scores were associated with increased internalizing (β = 0.40; 95% CI 0.14-0.68) and externalizing traits (β = 0.83; 95% CI 0.56-1.1). Urine metabolite scores were associated with internalizing (β = 0.42; 95% CI 0.16-0.68) and externalizing traits (β = 0.69; 95% CI 0.43-0.95), while the association with ADHD traits was nominal (β = 0.25; 95% CI: 0.006-0.502; nominal p = 0.045; BH-FDR p = 0.054). Associations were stable over time for internalizing and ADHD but weakened with age for externalizing traits.Conclusions
This proof-of-concept study shows that complementary serum and urine metabolomic profiles in early childhood are associated with subsequent internalizing and externalizing trait trajectories, while a nominal longitudinal association was observed between the urine metabolite profile and ADHD traits. These findings warrant evaluation in larger independent studies.
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BibTeX
@article{barmpa2026early,
title = {{Early childhood serum and urine metabolite signatures of internalizing, externalizing, and ADHD traits and their trajectories to adolescence: the Rhea mother-child cohort.}},
author = {Eleni Barmpa and Katerina Koutra and Chrysi Mouatsou and Katerina Margetaki and Mariza Kampouri and Ariadni Konopidou and Anastasia Chrysovalantou Chatziioannou and Konstantinos K Tsilidis and Martine Vrijheid and Lea Maitre and Hector C Keun and Manolis Kogevinas and Marianna Karachaliou and Christopher Papandreou},
journal = {Metabolomics : Official journal of the Metabolomic Society},
year = {2026},
month = oct,
doi = {10.1007/s11306-026-02550-1},
url = {https://europepmc.org/article/MED/42961540},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Early childhood serum and urine metabolite signatures of internalizing, externalizing, and ADHD traits and their trajectories to adolescence: the Rhea mother-child cohort.
AU - Eleni Barmpa
AU - Katerina Koutra
AU - Chrysi Mouatsou
AU - Katerina Margetaki
AU - Mariza Kampouri
AU - Ariadni Konopidou
AU - Anastasia Chrysovalantou Chatziioannou
AU - Konstantinos K Tsilidis
AU - Martine Vrijheid
AU - Lea Maitre
AU - Hector C Keun
AU - Manolis Kogevinas
AU - Marianna Karachaliou
AU - Christopher Papandreou
PY - 2026
DA - 2026/10/30
JO - Metabolomics : Official journal of the Metabolomic Society
DO - 10.1007/s11306-026-02550-1
UR - https://europepmc.org/article/MED/42961540
AB - Introduction Early-life emotional and behavioral difficulties increase vulnerability to later psychopathology, but it remains unclear whether a biological footprint is detectable in early childhood.Objectives We aimed to identify serum- and urine-based metabolite signatures of internalizing, externalizing, and attention-deficit/hyperactivity disorder (ADHD) traits in 6-year-old children and examine their associations with traits through adolescence.Methods We analyzed 196 participants of the Rhea cohort (Greece), with serum and urine metabolomics at age 6 and internalizing, externalizing, and ADHD traits assessed at ages 6, 11, and 15. Trait- and biofluid-specific metabolite signatures were identified using elastic net regression with cross-validation. Associations with subsequent traits at repeated time points were evaluated using confounder-adjusted linear mixed-effects models.Results Metabolite signatures comprising amino acids, acylcarnitines, phosphatidylcholines, and gut microbiota-related metabolites were identified for internalizing, externalizing, and ADHD traits. Serum metabolite scores were associated with increased internalizing (β = 0.40; 95% CI 0.14-0.68) and externalizing traits (β = 0.83; 95% CI 0.56-1.1). Urine metabolite scores were associated with internalizing (β = 0.42; 95% CI 0.16-0.68) and externalizing traits (β = 0.69; 95% CI 0.43-0.95), while the association with ADHD traits was nominal (β = 0.25; 95% CI: 0.006-0.502; nominal p = 0.045; BH-FDR p = 0.054). Associations were stable over time for internalizing and ADHD but weakened with age for externalizing traits.Conclusions This proof-of-concept study shows that complementary serum and urine metabolomic profiles in early childhood are associated with subsequent internalizing and externalizing trait trajectories, while a nominal longitudinal association was observed between the urine metabolite profile and ADHD traits. These findings warrant evaluation in larger independent studies.
SN - 1573-3882
SN - 1573-3890
ER -