Discovery of biochemical biomarkers for aggression: A role for metabolomics in psychiatry

Hagenbeek, Fiona A.; Kluft, C.; Hankemeier, Thomas; Bartels, Meike; Draisma, Harmen H.M.; Middeldorp, Christel M.; Berger, Ruud; Noto, Antonio; Lussu, Milena; Pool, René; Fanos, Vassilios; Boomsma, Dorret I.

doi:10.1002/ajmg.b.32435

Cited by 42 publications

(38 citation statements)

References 136 publications

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“…Furthermore, untargeted metabolomics is a method that is independent of priori assumptions, which could provide a holistic approach to understanding the phenotype [39]. To our knowledge, studies have reported metabolome studies of violence in animal models [40][41][42], but none in schizophrenia patients. Consequently, we speculate that schizophrenia patients with violence (V.SC) might differ from schizophrenia patients without violence (NV.SC) in metabolic phenotype.…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of amino acids and lipids metabolism in schizophrenia with violence

Chen

Tang³

et al. 2020

BMC Psychiatry

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Background: Many studies have related biochemical characteristics to violence and have reported schizophrenia could elevated the risk of violent behaviour. However, the metabolic characteristics of schizophrenia patients with violence (V.SC) are unclear. Methods: To explore the metabolic characteristics of schizophrenia with violence and to identify potential biomarkers, untargeted metabolomics was performed by using gas chromatography time-of-flight mass spectrometry to analyse the plasma metabolites of fifty-three V.SC and twenty-four schizophrenia patients without violence (NV.SC). Multivariate and univariate analyses were performed to identify differential metabolites and biomarkers. Violence was assessed by the MacArthur Violence Assessment Study method. Psychiatric symptoms were assessed by the Positive and Negative Syndrome Scale. Results: Multivariate analysis was unable to distinguish V.SC from NV.SC. Glycerolipid metabolism and phenylalanine, tyrosine and tryptophan biosynthesis were the differential metabolic pathways between V.SC and NV.SC. We confirmed ten metabolites and five metabolites as metabolic biomarkers of V.SC by random forest and support vector machine analysis, respectively. The biomarker panel, including the ratio of L-asparagine to L-aspartic acid, vanillylmandelic acid and glutaric acid, yielded an area under the receiver operating characteristic curve of 0.808. Conclusions: This study gives a holistic view of the metabolic phenotype of schizophrenia with violence which is characterized by the dysregulation of lipids and amino acids. These results might provide information for the aetiological understanding and management of violence in schizophrenia; however, this is a preliminary metabolomics study about schizophrenia with violence, which needs to be repeated in future studies.

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Section: Introductionmentioning

confidence: 99%

Dysregulation of amino acids and lipids metabolism in schizophrenia with violence

Chen

Tang³

et al. 2020

BMC Psychiatry

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“…Dopamine is widely considered to be a key player in the neurobiology of aggressive behavior (Hagenbeek et al, ). Its uptake from the synaptic cleft is modulated by the dopamine receptor family, encoded by genes DRD1 through to DRD5 .…”

Section: Discussionmentioning

confidence: 99%

DRD4 methylation as a potential biomarker for physical aggression: An epigenome‐wide, cross‐tissue investigation

Cecil

Walton

Pingault

et al. 2018

American J of Med Genetics Pt B

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Epigenetic processes that regulate gene expression, such as DNA methylation (DNAm), have been linked to individual differences in physical aggression. Yet, it is currently unclear whether:(a) DNAm patterns in humans associate with physical aggression independently of other cooccurring psychiatric and behavioral symptoms; (b) whether these patterns are observable across multiple tissues; and (c) whether they may function as a causal versus noncausal biomarker of physical aggression. Here, we used a multisample, cross-tissue design to address these questions. First, we examined genome-wide DNAm patterns (buccal swabs; Illumina 450k) associated with engagement in physical fights in a sample of high-risk youth (n = 119; age = 16-24 years; 53% female). We identified one differentially methylated region in DRD4, which survived genome-wide correction, associated with physical aggression above and beyond co-occurring symptomatology (e.g., ADHD, substance use), and showed strong cross-tissue concordance with both blood and brain. Second, we found that DNAm sites within this region were also differentially methylated in an independent sample of young adults, between individuals with a history of chronic-high versus low physical aggression (peripheral T cells; ages 26-28). Finally, we ran a Mendelian randomization analysis using GWAS data from the EAGLE consortium to test for a causal association of DRD4 methylation with physical aggression. Only one genetic instrument was eligible for the analysis, and results provided no evidence for a causal association. Overall, our findings lend support for peripheral DRD4 methylation as a potential biomarker of physically aggressive behavior, with no evidence yet of a causal relationship. K E Y W O R D S DNA methylation, DRD4, externalizing problems, Mendelian randomization, physical aggression, replication † Co-senior authors.

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“…Of note, this gloomy scenario applies also to biomarkers pertaining to neurochemical and metabolic pathways other than 5-HT one [15]. One possible explanation for the absence of validated biomarkers of aggression lies in the substantial heterogeneity of clinical (phenotypic) trait and in its multifactorial nature.…”

Section: Neurobiological Basis Of Aggressive/violent Behavior: Insighmentioning

confidence: 99%

Preventing Aggressive/Violent Behavior: A Role for Biomarkers?

Pinna

Manchia

2017

Biomark. Med.

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The burden of aggressive/violent behavior Despite a declining rate in the past 10 years, aggressive/violent behavior remains among the main causes of worldwide premature mortality [1]. Associated direct (medical and nonmedical expenditure) and indirect (longterm societal implications) socio-economic costs are also substantial [2,3]. These have been estimated in 2001 at approximately 5% of the gross national product of industrialized countries, and as much as 14% of the gross national product of low-income countries [3].In this context, policy makers have attempted to enact interventions that could prevent the development of aggression and violence in at-risk populations (i.e., abused children and troubled youth, alcohol and substance abusers, prisoners). These public health approaches that include, among the others, education, behavior change, policy, engineering and environmental support, have proven to be effective in reducing the rates of aggression/violence as well as its associated economic costs [4].Nonetheless, there is still a substantial proportion of individuals who enact aggressive/violent behavior over the lifetime course that is not targeted by these interventions. Further, such interventions are implemented only once aggressive behavior has already manifested itself.By definition, primary preventive strategies intend to avoid the manifestation of a specific disease or event before it occurs. To be effective, preventive approaches need to identify risk factors that can determine the onset of an illness or of an event in an exposed population.In the case of aggressive/violent behavior, there is a multitude of determinants (clinical, environmental and biological) that set the liability threshold for its manifestation. It is plausible that predictive models integrating different levels of information (from phenotypic to 'omics' data) might help identifying with higher accuracy individuals at risk for aggression/violence compared with those relying only, for instance, on clinical data. However, the inclusion of biological markers (henceforth biomarkers) in such models can be achieved only if they are identified in longitudinal prospective studies and are replicated in independent samples. Importantly, this process could also lead to a more precise understanding of the neurobiological underpinnings of aggression/violence.Here, we critically discuss the recent advancements in the identification of biological markers of aggression and the eventual barriers toward their implementation in predictive models. To this end, we will first briefly present the current knowledge on the neurobiological make up of aggression/violent behavior. Next, we will discuss how the phenotypic heterogeneity of aggression might have hindered the identification of reliable biomarkers. Finally, we will present data on available biological markers of aggression that might be suitable for implementation in predictive models.

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Discovery of biochemical biomarkers for aggression: A role for metabolomics in psychiatry

Cited by 42 publications

References 136 publications

Dysregulation of amino acids and lipids metabolism in schizophrenia with violence

Dysregulation of amino acids and lipids metabolism in schizophrenia with violence

DRD4 methylation as a potential biomarker for physical aggression: An epigenome‐wide, cross‐tissue investigation

Preventing Aggressive/Violent Behavior: A Role for Biomarkers?

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