NEUROGENETICS, SEROTONIN, AND HUMAN AGGRESSION

攻击性是许多临床疾病(如反社会人格障碍)的突出特征，是刑事监禁的常见原因，并经常伴随酒精和其他药物滥用。与攻击性行为相关的社会成本也是当代社会主要关注的问题之一。除了环境决定因素外，遗传因素也是导致攻击性气质的原因。正如临床、法医和非患者样本所见，中枢神经系统(CNS)5-羟色胺能活性降低也与人类攻击性有关。我们之前已经发现，在非患者群体中的无关个体中，攻击性和愤怒相关人格特征的生活史，以及中枢神经系统5-羟色胺能反应性，与调节5-羟色胺系统元素的两个基因的多态性有关：色氨酸羟基酶和单胺氧化酶A。拟议的研究的目的是通过更明确的方法来证实和扩展这些观察结果，利用基于家庭的对照结合对成年人、社区志愿者及其父母的传递不平衡(TDT)分析。主要研究样本将包括800人，包括通过标准化临床访谈评估的攻击性表型的人群分布的相对末端(四分位)。还将评估5-羟色胺能系统中的其他多态，如果发现非功能性多态的等位基因可以区分高侵袭性和低侵袭性受试者，将进行详细的分子分析，以确定可能解释这些关联的功能变异。研究参与者的精神病学特征将通过结构化的诊断性评估进行，攻击性行为的群体差异将通过额外的访谈、问卷和对抗性倾向和冲动的观察性测量来确认。这个项目的发现将促进对人类气质的一个重要维度与反社会行为、暴力、人际关系痛苦和人格相关精神病的遗传相关性的理解。本申请书是先前同名建议书的重新提交。

Aggression is a prominent feature of many clinical conditions (such as antisocial personality disorder), a common cause of criminal incarceration, and a frequent concomitant of alcohol and other substance abuse. The social costs associated with aggressive behavior also rank among the primary concerns of contemporary society. In addition to environmental determinants, genetic factors contribute to the etiology of aggressive temperament. Reduced central nervous system (CNS) serotonergic activity is also correlated with human aggression, as seen in clinical, forensic and non patient samples. We have previously found that among unrelated individuals in a non patient population, life history of aggression and anger-related personality traits, as well as CNS serotonergic responsivity, are associated with polymorphisms of two genes regulating elements of the serotonergic system: tryptophan hydroxylase and monoamine oxidase A. The purpose of the proposed research is to confirm and extend these observations by more definitive methodology, utilizing family-based controls in conjunction with transmission-disequilibrium (TDT) analysis of adult, community volunteers and their parents. The primary study sample will include 800 individuals comprising relative ends (quartiles) of the population distribution of aggressive phenotype, as assessed by standardized clinical interview. Additional polymorphisms in the serotonergic system will also be evaluated, and if alleles of non-functional polymorphisms are found to differentiate high and low aggressive subjects, detailed molecular analyses will be conducted to identify functional variation that may account for these associations. Psychiatric characterization of study participants will be made by structured diagnostic evaluation and group differences in aggressive behavior will be confirmed by additional interview, questionnaire and observational measures of antagonistic disposition and impulsivity. The findings of this project will advance understanding of the genetic correlates of an important dimension of human temperament germane to antisocial behavior, violence, interpersonal distress, and personality-related psychopathology. This application is the resubmission of a prior proposal of the same title.