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

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

doi:10.3389/fpsyt.2020.00165

Cited by 24 publications

(41 citation statements)

References 70 publications

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“…To our knowledge, this is the first time ketone bodies, and 3-hydroxybutyrate specifically, have been associated with aggression. In a urinary metabolite study with aggression in the NTR, no significant associations were found, but several near-significant results pointed to energy metabolism as a potential group of metabolites warranting further investigation 22 . Additionally, there are two recent studies showing a link between 3-hydroxybutyrate and depression, one in mice that was negatively correlated 18 and one in humans that was positively correlated 19 .…”

Section: Discussionmentioning

confidence: 93%

“…Associations between lipid concentrations and aggression have previously been noted 6 , 12 – 15 , while other low-molecular-weight molecules might hold more promise for novel findings. Amino acids and ketone bodies (low-molecular-weight molecules categorized in NMR) have been associated with emotional and behavioural problems other than aggression 16 – 20 , and some studies have shown amino acids and similar molecules associated with anger and psychopathy 21 , schizophrenia-related violence 15 , and childhood aggression 22 . Accordingly, these areas offered a reasonable place to focus our exploratory investigation.…”

Section: Introductionmentioning

confidence: 99%

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Ketone body 3-hydroxybutyrate as a biomarker of aggression

Whipp

Vuoksimaa

Korhonen

et al. 2021

Sci Rep

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Human aggression is a complex behaviour, the biological underpinnings of which remain poorly known. To gain insights into aggression biology, we studied relationships with aggression of 11 low-molecular-weight metabolites (amino acids, ketone bodies), processed using 1H nuclear magnetic resonance spectroscopy. We used a discovery sample of young adults and an independent adult replication sample. We studied 725 young adults from a population-based Finnish twin cohort born 1983–1987, with aggression levels rated in adolescence (ages 12, 14, 17) by multiple raters and blood plasma samples at age 22. Linear regression models specified metabolites as the response variable and aggression ratings as predictor variables, and included several potential confounders. All metabolites showed low correlations with aggression, with only one—3-hydroxybutyrate, a ketone body produced during fasting—showing significant (negative) associations with aggression. Effect sizes for different raters were generally similar in magnitude, while teacher-rated (age 12) and self-rated (age 14) aggression were both significant predictors of 3-hydroxybutyrate in multi-rater models. In an independent replication sample of 960 adults from the Netherlands Twin Register, higher aggression (self-rated) was also related to lower levels of 3-hydroxybutyrate. These exploratory epidemiologic results warrant further studies on the role of ketone metabolism in aggression.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Ketone body 3-hydroxybutyrate as a biomarker of aggression

Whipp

Vuoksimaa

Korhonen

et al. 2021

Sci Rep

View full text Add to dashboard Cite

show abstract

“…To our knowledge, this is the first time ketone bodies, and 3-hydroxybutyrate specifically, have been associated with aggression. In a urinary metabolite study with aggression in the NTR, no significant associations were found, but several near-significant results pointed to energy metabolism as a potential group of metabolites warranting further investigation [19]. Additionally, there are two recent studies showing a link between 3-hydroxybutyrate and depression, one in mice that was negatively correlated [16] and one in humans that was positively correlated [17].…”

Section: Discussionmentioning

confidence: 99%

“…Regarding biomarker stability, while we do see high heritability in the energy metabolism biomarkers (53.2% for 3-hydroxybutyrate) [47], it would also be important in future studies to have repeated biological samples to confirm the stability of this biomarker over time, concurrent with the stability of aggression measures. However, repeated blood samples from children may be challenging to obtain, and thus this work might need to be done in young adults first, or using less invasive samples such as urine or saliva, which might produce different results than plasma (the recent urine biomarker study on NTR children did not show any significant findings with 3-hydroxybutyric acid and aggression) [19].…”

Section: Discussionmentioning

confidence: 99%

Ketone body 3-hydroxybutyrate: a biomarker of aggression?

Whipp

Vuoksimaa

Korhonen

et al. 2020

Preprint

Self Cite

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Human aggression is a complex behavior, the biological underpinnings of which remain poorly known. To gain insights into aggression biology, we studied relationships with aggression of 11 low-molecular-weight metabolites (amino acids, ketone bodies), processed using 1H nuclear magnetic resonance spectroscopy. We used a discovery sample of young adults and an independent adult replication sample. We studied 725 young adults from a population-based Finnish twin cohort born 1983-87, with aggression levels rated in adolescence (ages 12, 14, 17) by multiple raters and blood plasma samples at age 22. Linear regression models specified metabolites as the dependent and aggression ratings as independent variables, and included several fixed effects. All metabolites showed low correlations with aggression, with only one - 3-hydroxybutyrate, a ketone body produced during fasting - showing significant (negative) associations with aggression. Effect sizes for different raters were generally similar in magnitude, while teacher-rated (age 12) and self-rated aggression (age 14) were both significant predictors of 3-hydroxybutyrate in multi-rater models. In an independent replication sample of 960 adults from the Netherlands Twin Register, higher self-rated aggression was also related to lower levels of 3-hydroxybutyrate. These exploratory epidemiologic results warrant further studies on the role of ketone metabolism in aggression.

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“…This study is embedded in a larger project on childhood aggression: Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies (ACTION) [65,66]. From the population-based NTR, the ACTION study identified twins who at least once scored higher or lower on a sum score for aggression [67,68].…”

Section: Methodsmentioning

confidence: 99%

DNA Methylation Signatures of Breastfeeding in Buccal Cells Collected in Mid-Childhood

et al. 2019

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Breastfeeding has long-term benefits for children that may be mediated via the epigenome. This pathway has been hypothesized, but the number of empirical studies in humans is small and mostly done by using peripheral blood as the DNA source. We performed an epigenome-wide association study (EWAS) in buccal cells collected around age nine (mean = 9.5) from 1006 twins recruited by the Netherlands Twin Register (NTR). An age-stratified analysis examined if effects attenuate with age (median split at 10 years; n<10 = 517, mean age = 7.9; n>10 = 489, mean age = 11.2). We performed replication analyses in two independent cohorts from the NTR (buccal cells) and the Avon Longitudinal Study of Parents and Children (ALSPAC) (peripheral blood), and we tested loci previously associated with breastfeeding in epigenetic studies. Genome-wide DNA methylation was assessed with the Illumina Infinium MethylationEPIC BeadChip (Illumina, San Diego, CA, USA) in the NTR and with the HumanMethylation450 Bead Chip in the ALSPAC. The duration of breastfeeding was dichotomized (‘never‘ vs. ‘ever’). In the total sample, no robustly associated epigenome-wide significant CpGs were identified (α = 6.34 × 10–8). In the sub-group of children younger than 10 years, four significant CpGs were associated with breastfeeding after adjusting for child and maternal characteristics. In children older than 10 years, methylation differences at these CpGs were smaller and non-significant. The findings did not replicate in the NTR sample (n = 98; mean age = 7.5 years), and no nearby sites were associated with breastfeeding in the ALSPAC study (n = 938; mean age = 7.4). Of the CpG sites previously reported in the literature, three were associated with breastfeeding in children younger than 10 years, thus showing that these CpGs are associated with breastfeeding in buccal and blood cells. Our study is the first to show that breastfeeding is associated with epigenetic variation in buccal cells in children. Further studies are needed to investigate if methylation differences at these loci are caused by breastfeeding or by other unmeasured confounders, as well as what mechanism drives changes in associations with age.

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

Cited by 24 publications

References 70 publications

Ketone body 3-hydroxybutyrate as a biomarker of aggression

Ketone body 3-hydroxybutyrate as a biomarker of aggression

Ketone body 3-hydroxybutyrate: a biomarker of aggression?

DNA Methylation Signatures of Breastfeeding in Buccal Cells Collected in Mid-Childhood

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