DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan

Abstract

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N=15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha=1.2×10−7; Bonferroni correction). In cord blood samples of 2,425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r=0.74, p=0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripherl blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range=3-82%) of the aggression–methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.

Integrative multi-omics analysis of childhood aggressive behavior

“…The CpGs in the single- or multi-omics models did not overlap with the top differentially methylated CpGs for physical aggression as observed in buccal-cells (Cecil et al 2018b), and were not significantly associated with aggression in a recent blood-based EWAS meta-analysis (van Dongen et al 2021). That our models selected no CpGs overlapping with these studies was unsurprising, since it was previously shown that the top CpGs from these studies were not associated with aggressive behavior in the buccal DNA methylation data in the NTR and LUMC-Curium cohorts (van Dongen et al 2021).…”

“…The CpGs in the single- or multi-omics models did not overlap with the top differentially methylated CpGs for physical aggression as observed in buccal-cells (Cecil et al 2018b), and were not significantly associated with aggression in a recent blood-based EWAS meta-analysis (van Dongen et al 2021). That our models selected no CpGs overlapping with these studies was unsurprising, since it was previously shown that the top CpGs from these studies were not associated with aggressive behavior in the buccal DNA methylation data in the NTR and LUMC-Curium cohorts (van Dongen et al 2021). Trait enrichment of the CpGs selected by the single- and multi-omics models reported enrichment of known aggression risk factors, such as socioeconomic status (Miller and Tolan 2019; Bellair et al 2019; Hendriks et al 2020), childhood malnutrition (Liu 2004; Vaughn et al 2016), and pre-and perinatal risk factors (Van Adrichem et al 2020).…”

“…The ACTION Biomarker Study comprised a cohort of twins from the Netherlands Twin Register (NTR) (Ligthart et al 2019) and a clinical cohort of children referred to a youth psychiatry clinic (LUMC-Curium, the Netherlands). The genome-wide SNP and DNA methylation (Illumina EPIC 850K array) data, and the urinary amines and organic acids as measured in these cohorts were previously included in a genome-wide genetic and epigenetic association study and a metabolomics study of (childhood) aggression (Hagenbeek et al 2020;van Dongen et al 2021;Ip et al 2021). We expand on these single-omics studies by integrating these data with a third metabolomics dataset, focusing on urinary steroid hormones.…”

“…Small-scale epigenetic studies (sample size range: 41-260) showed that DNA methylation differences in various tissues are associated with aggression and related traits in children and adults (Guillemin et al 2014; Cecil et al 2018b, a; Mitjans et al 2019). 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).…”

Systemic interindividual epigenetic variation in humans is associated with transposable elements and under strong genetic control

“…Nearly all these epigenome-wide association studies (EWAS) used commercial arrays manufactured by Illumina (predominantly the HM450 and subsequently the scaled-up EPIC850 array) to assess methylation at CpG dinucleotides (a highly stable epigenetic mark) in peripheral blood DNA (6, 7). EWAS have uncovered associations between blood DNA methylation and neurological outcomes including Alzheimer’s disease (8), neurodegenerative disorders (9), educational attainment (10), and psychiatric diseases (11). The HM450 and EPIC arrays were instrumental in discoveries in epigenetic aging (12–14), smoking-induced DNA methylation alterations (15), and understanding how maternal smoking (16) and alcohol consumption (17) affect DNA methylation in newborns.…”