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

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

doi:10.3389/fpsyt.2020.00165

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

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

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

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 (N = 1,347) and clinic-referred children (N = 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 (N = 783); a replication phase in twin pairs discordant for aggression (N = 378); and a validation phase in clinical cases and matched twin controls (N = 367). In the discovery phase, 6 biomarkers were significantly associated with childhood aggression, of which the association of O-phosphoserine (β = 0.36; SE = 0.09; p = 0.004), and gamma-L-glutamyl-L-alanine (β = 0.32; SE = 0.09; p = 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.

Original language	English
Article number	165
Journal	Frontiers in Psychiatry
Volume	11
DOIs	https://doi.org/10.3389/fpsyt.2020.00165
Publication status	Published - 31 Mar 2020

Funding

The Netherlands Twin Register (NTR) very warmly thanks all twins and their family members for their participation. We acknowledge the contributions of Anne M. Hendriks, Josephine Oomkens, Maarten J. Schouten, Daphne S. Snel, Yayouk E. Willems, and Matthijs D. van der Zee in the data collection for the ACTION project in the NTR. Curium-LUMC thanks all patients and their parents for participating, and clinicians for their support. We acknowledge the contributions of all students in the data collection for the ACTION project in Curium-LUMC. We thank Anne M. Hendriks and Hill F. Ip (Vrije Universiteit Amsterdam) for proofreading the first draft of the manuscript and their helpful comments. Preliminary analyses of this paper were included in a presentation at the ACTION final meeting on aggression studies in May 2019 on Sardinia, Italy. Funding. This current work was supported by the Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies project (ACTION). ACTION received funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement no 602768. The Netherlands Twin Register was supported by grant NWO 480-15-001/674: Netherlands Twin Registry Repository: researching the interplay between genome and environment, the Avera Institute for Human Genetics and by multiple grants from the Netherlands Organization for Scientific Research (NWO), and the Royal Netherlands Academy of Science Professor Award (PAH/6635) to DB. MB was supported by an ERC consolidator grant (WELL-BEING 771057 PI Bartels).

Funders	Funder number
Avera Institute for Human Genetics
NTR
European Commission
Seventh Framework Programme
European Research Council
Horizon 2020 Framework Programme	771057
Seventh Framework Programme	602768, NWO 480-15-001/674
Royal Netherlands Academy of Science	PAH/6635
Not added	480-15-001

Keywords

amines
biomarkers
childhood aggression
metabolites
metabolomics
neurotransmitters
organic acids
oxidative stress

Cohort Studies

Netherlands Twin Register (NTR)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3389/fpsyt.2020.00165

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Hagenbeek, F. A., Roetman, P. J., Pool, R., Kluft, C., Harms, A. C., van Dongen, J., Colins, O. F., Talens, S., van Beijsterveldt, C. E. M., Vandenbosch, M. M. L. J. Z., de Zeeuw, E. L., Déjean, S., Fanos, V., Ehli, E. A., Davies, G. E., Hottenga, J. J., Hankemeier, T., Bartels, M., Vermeiren, R. R. J. M., & Boomsma, D. I. (2020). Urinary Amine and Organic Acid Metabolites Evaluated as Markers for Childhood Aggression: The ACTION Biomarker Study. Frontiers in Psychiatry, 11, Article 165. https://doi.org/10.3389/fpsyt.2020.00165

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abstract = "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 (N = 1,347) and clinic-referred children (N = 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 (N = 783); a replication phase in twin pairs discordant for aggression (N = 378); and a validation phase in clinical cases and matched twin controls (N = 367). In the discovery phase, 6 biomarkers were significantly associated with childhood aggression, of which the association of O-phosphoserine (β = 0.36; SE = 0.09; p = 0.004), and gamma-L-glutamyl-L-alanine (β = 0.32; SE = 0.09; p = 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.",

keywords = "amines, biomarkers, childhood aggression, metabolites, metabolomics, neurotransmitters, organic acids, oxidative stress",

author = "Hagenbeek, {Fiona A.} and Roetman, {Peter J.} and Ren{\'e} Pool and Cornelis Kluft and Harms, {Amy C.} and {van Dongen}, Jenny and Colins, {Olivier F.} and Simone Talens and {van Beijsterveldt}, {Catharina E.M.} and Vandenbosch, {Marjolein M.L.J.Z.} and {de Zeeuw}, {Eveline L.} and S{\'e}bastien D{\'e}jean and Vassilios Fanos and Ehli, {Erik A.} and Davies, {Gareth E.} and Hottenga, {Jouke Jan} and Thomas Hankemeier and Meike Bartels and Vermeiren, {Robert R.J.M.} and Boomsma, {Dorret I.}",

year = "2020",

month = mar,

day = "31",

doi = "10.3389/fpsyt.2020.00165",

language = "English",

volume = "11",

journal = "Frontiers in Psychiatry",

issn = "1664-0640",

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Hagenbeek, FA, Roetman, PJ, Pool, R, Kluft, C, Harms, AC, van Dongen, J, Colins, OF, Talens, S, van Beijsterveldt, CEM, Vandenbosch, MMLJZ, de Zeeuw, EL, Déjean, S, Fanos, V, Ehli, EA, Davies, GE, Hottenga, JJ, Hankemeier, T, Bartels, M, Vermeiren, RRJM & Boomsma, DI 2020, 'Urinary Amine and Organic Acid Metabolites Evaluated as Markers for Childhood Aggression: The ACTION Biomarker Study', Frontiers in Psychiatry, vol. 11, 165. https://doi.org/10.3389/fpsyt.2020.00165

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T1 - Urinary Amine and Organic Acid Metabolites Evaluated as Markers for Childhood Aggression

T2 - The ACTION Biomarker Study

AU - Hagenbeek, Fiona A.

AU - Roetman, Peter J.

AU - Pool, René

AU - Kluft, Cornelis

AU - Harms, Amy C.

AU - van Dongen, Jenny

AU - Colins, Olivier F.

AU - Talens, Simone

AU - van Beijsterveldt, Catharina E.M.

AU - Vandenbosch, Marjolein M.L.J.Z.

AU - de Zeeuw, Eveline L.

AU - Déjean, Sébastien

AU - Fanos, Vassilios

AU - Ehli, Erik A.

AU - Davies, Gareth E.

AU - Hottenga, Jouke Jan

AU - Hankemeier, Thomas

AU - Bartels, Meike

AU - Vermeiren, Robert R.J.M.

AU - Boomsma, Dorret I.

PY - 2020/3/31

Y1 - 2020/3/31

N2 - 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 (N = 1,347) and clinic-referred children (N = 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 (N = 783); a replication phase in twin pairs discordant for aggression (N = 378); and a validation phase in clinical cases and matched twin controls (N = 367). In the discovery phase, 6 biomarkers were significantly associated with childhood aggression, of which the association of O-phosphoserine (β = 0.36; SE = 0.09; p = 0.004), and gamma-L-glutamyl-L-alanine (β = 0.32; SE = 0.09; p = 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.

AB - 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 (N = 1,347) and clinic-referred children (N = 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 (N = 783); a replication phase in twin pairs discordant for aggression (N = 378); and a validation phase in clinical cases and matched twin controls (N = 367). In the discovery phase, 6 biomarkers were significantly associated with childhood aggression, of which the association of O-phosphoserine (β = 0.36; SE = 0.09; p = 0.004), and gamma-L-glutamyl-L-alanine (β = 0.32; SE = 0.09; p = 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.

KW - amines

KW - biomarkers

KW - childhood aggression

KW - metabolites

KW - metabolomics

KW - neurotransmitters

KW - organic acids

KW - oxidative stress

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U2 - 10.3389/fpsyt.2020.00165

DO - 10.3389/fpsyt.2020.00165

M3 - Article

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SN - 1664-0640

VL - 11

JO - Frontiers in Psychiatry

JF - Frontiers in Psychiatry

M1 - 165

ER -

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

Abstract

Funding

Keywords

Cohort Studies

UN SDGs

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