Monoamine and neuroendocrine gene-sets associate with frustration-based aggression in a gender-specific manner.

Investigating phenotypic heterogeneity in aggression and understanding the molecular biological basis of aggression subtypes may lead to new prevention and treatment options. In the current study, we evaluated the taxonomy of aggression and examined specific genetic mechanisms underlying aggression subtypes in healthy males and females. Confirmatory Factor Analysis (CFA) was used to replicate a recently reported three-factor model of the Reactive Proactive Questionnaire (RPQ) in healthy adults (n=661; median age 24.0 years; 41% male). Gene-set association analysis, aggregating common genetic variants within (a combination of) three molecular pathways previously implicated in aggression, i.e. serotonergic, dopaminergic, and neuroendocrine signaling, was conducted with MAGMA software in males and females separately (total n=395) for aggression subtypes. We replicate the three-factor CFA model of the RPQ, and found males to score significantly higher on one of these factors compared to females: proactive aggression. The genetic association analysis showed a female-specific association of genetic variation in the combined gene-set with a different factor of the RPQ; reactive aggression due to internal frustration. Both the neuroendocrine and serotonergic gene-sets contributed significantly to this association. Our genetic findings are subtype- and sex-specific, stressing the value of efforts to reduce heterogeneity in research of aggression etiology. Importantly, subtype- and sex-differences in the underlying pathophysiology of aggression suggest that optimal treatment options will have to be tailored to the individual patient. Male and female needs of intervention might differ, stressing the need for sex-specific further research of aggression. Our work highlights opportunities for sample size maximization offered by population-based studies of aggression.