Genome‐wide DNA methylation analysis of aggressive behaviour: a longitudinal population‐based study

Abstract

Background Human aggression is influenced by an interplay between genetic predisposition and experience across the life span. This interaction is thought to occur through epigenetic mechanisms, inducing differential gene expression, thereby moderating neuronal cell and circuit function, and thus shaping aggressive behaviour. Methods Genome‐wide DNA methylation (DNAm) levels were measured in peripheral blood obtained from 95 individuals participating in the Estonian Children Personality Behaviours and Health Study (ECPBHS) at 15 and 25 years of age. We examined the association between aggressive behaviour, as measured by Life History of Aggression (LHA) total score and DNAm levels both assessed at age 25. We further examined the pleiotropic effect of genetic variants regulating LHA‐associated differentially methylated positions (DMPs) and multiple traits related to aggressive behaviours. Lastly, we tested whether the DNA methylomic loci identified in association with LHA at age 25 were also present at age 15. Results We found one differentially methylated position (DMP) (cg17815886; p = 1.12 × 10−8) and five differentially methylated regions (DMRs) associated with LHA after multiple testing adjustments. The DMP annotated to the PDLIM5 gene, and DMRs resided in the vicinity of four protein‐encoding genes (TRIM10, GTF2H4, SLC45A4, B3GALT4) and a long intergenic non‐coding RNA (LINC02068). We observed evidence for the colocalization of genetic variants associated with top DMPs and general cognitive function, educational attainment and cholesterol levels. Notably, a subset of the DMPs associated with LHA at age 25 also displayed altered DNAm patterns at age 15 with high accuracy in predicting aggression. Conclusions Our findings highlight the potential role of DNAm in the development of aggressive behaviours. We observed pleiotropic genetic variants associated with identified DMPs, and various traits previously established to be relevant in shaping aggression in humans. The concordance of DNAm signatures in adolescents and young adults may have predictive value for inappropriate and maladaptive aggression later in life.

Effect of RNA m6A methyltransferase activation by a low molecular weight compound on anxiety- and depression-related behaviours, monoamine neurochemistry and striatal gene expression in the rat

“…Triggering of the pathogenetic cascade by life events and maintenance of the new meta-stable state of the CNS is likely to be mediated by multiple epigenetic and downstream regulatory mechanisms. Epigenetic DNA modifications, especially DNA methylation, in psychiatric conditions such as affective, anxiety and substance use disorders or aggressiveness have garnered much scrutiny in recent years (Juruena et al, 2021; Panariello et al, 2022; Harvanek et al, 2023; Persaud and Cates, 2023; Pishva et al, 2023). However, limited attention has been paid to modification of mRNA by methylation.…”