AUTHOR=Hagenbeek Fiona A. , Roetman Peter J. , Pool René , Kluft Cornelis , Harms Amy C. , van Dongen Jenny , Colins Olivier F. , Talens Simone , van Beijsterveldt Catharina E. M. , Vandenbosch Marjolein M. L. J. Z. , de Zeeuw Eveline L. , Déjean Sébastien , Fanos Vassilios , Ehli Erik A. , Davies Gareth E. , Hottenga Jouke Jan , Hankemeier Thomas , Bartels Meike , Vermeiren Robert R. J. M. , Boomsma Dorret I. 

TITLE=Urinary Amine and Organic Acid Metabolites Evaluated as Markers for Childhood Aggression: The ACTION Biomarker Study

JOURNAL=Frontiers in Psychiatry

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2020.00165

DOI=10.3389/fpsyt.2020.00165

ISSN=1664-0640

ABSTRACT=<p>Biomarkers are of interest as potential diagnostic and predictive instruments in personalized medicine. We present the first urinary metabolomics biomarker study of childhood aggression. We aim to examine the association of urinary metabolites and neurotransmitter ratios involved in key metabolic and neurotransmitter pathways in a large cohort of twins (<italic>N</italic> = 1,347) and clinic-referred children (<italic>N</italic> = 183) with an average age of 9.7 years. This study is part of ACTION (Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies), in which we developed a standardized protocol for large-scale collection of urine samples in children. Our analytical design consisted of three phases: a discovery phase in twins scoring low or high on aggression (<italic>N</italic> = 783); a replication phase in twin pairs discordant for aggression (<italic>N</italic> = 378); and a validation phase in clinical cases and matched twin controls (<italic>N</italic> = 367). In the discovery phase, 6 biomarkers were significantly associated with childhood aggression, of which the association of O-phosphoserine (β = 0.36; <italic>SE</italic> = 0.09; <italic>p</italic> = 0.004), and gamma-L-glutamyl-L-alanine (β = 0.32; <italic>SE</italic> = 0.09; <italic>p</italic> = 0.01) remained significant after multiple testing. Although non-significant, the directions of effect were congruent between the discovery and replication analyses for six biomarkers and two neurotransmitter ratios and the concentrations of 6 amines differed between low and high aggressive twins. In the validation analyses, the top biomarkers and neurotransmitter ratios, with congruent directions of effect, showed no significant associations with childhood aggression. We find suggestive evidence for associations of childhood aggression with metabolic dysregulation of neurotransmission, oxidative stress, and energy metabolism. Although replication is required, our findings provide starting points to investigate causal and pleiotropic effects of these dysregulations on childhood aggression.</p>