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.

中文翻译：

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单胺和神经内分泌基因组以性别特异性方式与基于挫折的攻击性相关

研究侵略的表型异质性和了解侵略亚型的分子生物学基础可能会导致新的预防和治疗选择。在当前的研究中，我们评估了攻击性的分类并检查了健康男性和女性攻击性亚型的特定遗传机制。验证性因素分析 (CFA) 用于在健康成人（n=661；中位年龄 24.0 岁；41% 男性）中复制最近报道的反应性主动问卷 (RPQ) 的三因素模型。基因集关联分析，在先前与攻击性有关的三种分子途径（即血清素能、多巴胺能和神经内分泌信号传导）（组合）内聚合常见遗传变异，分别用 MAGMA 软件在男性和女性中进行（总共 n=395）的攻击亚型。我们复制了 RPQ 的三因素 CFA 模型，发现与女性相比，男性在以下因素之一上的得分明显更高：主动攻击。遗传关联分析表明，组合基因组中的遗传变异与 RPQ 的不同因素之间存在女性特异性关联；由于内部挫折而产生的反应性攻击。神经内分泌和血清素基因组都对这种关联有显着贡献。我们的基因发现具有亚型和性别特异性，强调了在攻击性病因研究中努力减少异质性的价值。重要的，攻击性潜在病理生理学的亚型和性别差异表明，必须针对个体患者量身定制最佳治疗方案。男性和女性对干预的需求可能不同，强调需要针对特定​​性别的攻击行为进行进一步研究。我们的工作强调了基于人口的攻击性研究提供的样本量最大化的机会。