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 2425 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 peripheral 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.
Highlights
Aggression encompasses a range of behaviors, such as bullying, verbal abuse, fighting, and destroying objects
In the combined meta-analysis of peripheral and cord blood data, methylation at 13 CpGs was associated with aggression after Bonferroni correction, including ten CpGs from the peripheral blood meta-analysis, and 43 passed a less conservative threshold (FDR 5%, Table 3)
We identified associations between aggressive behavior and DNA methylation in blood at CpGs whose methylation level is associated with exposure to smoking, alcohol consumption, other chemical exposures, and genetic variation
Summary
Aggression encompasses a range of behaviors, such as bullying, verbal abuse, fighting, and destroying objects. Life social conditions, including low parental income, separation from a parent, family dysfunction, and maternal smoking during pregnancy are risk factors for childhood aggression [1,2,3]. DNA methylation mediates effects of genetic variants in regulatory regions on gene expression [7] and is modifiable by early life social environment, as demonstrated by animal studies [8, 9], and by chemical exposures including (prenatal) exposure to cigarette smoke, as illustrated by numerous human studies [10]. Despite the large tissue-specificity of DNA methylation, effects of genetic variants on nearby DNA methylation (cis mQTLs) correlate strongly between blood and brain cells [11]. DNA methylation signatures of chemical exposures [12] and maternal rearinging [9] show a certain (but less understood) degree of conservation across tissues
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
