Ketone body 3-hydroxybutyrate: a biomarker of aggression?

Abstract

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.

Branched-chain amino acids linked to depression in young adults

“…A composite "combined" p factor score was also created by taking the mean of parent (12), teacher (12), and self ( 14) p factor values because we know that ratings from different raters are not highly correlated (Achenbach et al, 1987;Whipp et al, 2019Whipp et al, , 2021a. The combined p factor is used in initial analyses to reduce issues of multiple testing, as was applied in our previous aggression biomarker study (Whipp et al, 2021b).…”

“…Metabolomic investigations have been used in studies of somatic health conditions for many years and have more recently been used in psychiatry (Martins-de-Souza, 2014;Guest et al, 2016;Bot et al, 2020;Pu et al, 2021). Metabolomic approaches--in particular untargeted approaches, which use a broad panel of metabolite information to investigate associations--have been harnessed to generate new ideas and hypotheses in mental health (Bot et al, 2020;Whipp et al, 2021b), and continue to be useful in studies of depression.…”

“…In this study, we therefore aimed to use a panel of lowmolecular weight metabolites collected in young adulthood to investigate associations between biomarkers and depressive symptoms, as well as the p factor, in adolescence and young adulthood. In the p factor investigation, we also draw on findings from our previous study in the same dataset where we identified an association between ketone body 3hydroxybutyrate and aggressive behavior in adolescence and young adulthood (Whipp et al, 2021b). This study is also a part of the Equal-Life consortium--a consortium in the European Human Exposome Network--which aims to investigate the effect of the internal (e.g., biomarkers) and external (e.g., physical environment and socioeconomic indicators) exposome on mental health in children, from conception to young adulthood (van Kamp et al, 2022).…”

The genetic background of the associations between sense of coherence and mental health, self-esteem and personality

“…This evidence of overlap in genetic liability to individual variation in SOC with psychological well-being, dimensions of mental health and personality creates opportunities for further research. The search for endophenotypes that mediate effects of dispositional genes on observed phenotypes of psychopathology [44] can be extended to endophenotypic pathways for risk-relevant behavioral precursors as illustrated by a study suggesting a novel metabolic biomarker, ketone body 3-hydroxybutyrate, of aggression [45]. Such research is responsive to the call to create a holistic framework for enhanced understanding of mental health traits, proposed by the National Institute of Mental Health's Research Domain Criteria (RDoC) Initiative [46].…”

Integrative multi-omics analysis of childhood aggressive behavior

“…The first large-scale epigenome-wide association study (EWAS) meta-analysis across child and adult cohorts (N = 15,324) reported 13 significant sites in peripheral blood for broad aggression across the lifespan (van Dongen et al 2021). Metabolomics studies (sample size range: 77-725) detected plasma and serum metabolites associated with aggression and related traits in adults (Gulsun et al 2016; Chen et al 2020; Whipp et al 2021b). A study in 1,347 twins and 183 clinical cases found significant associations of urinary metabolites with childhood aggression (Hagenbeek et al 2020).…”