NEUROGENETICS, SEROTONIN, AND HUMAN AGGRESSION

攻击性是许多临床疾病（如反社会人格障碍）的一个突出特征，是刑事监禁的常见原因，也是酒精和其他物质滥用的常见伴随物。与攻击性行为相关的社会成本也是当代社会的主要关注点之一。除了环境因素外，遗传因素也是攻击性气质的病因。降低的中枢神经系统（CNS）多巴胺能活性也与人类攻击性相关，如在临床、法医和非患者样品中所见。我们以前发现，在非患者人群中的无关个体中，攻击性生活史和愤怒相关的人格特质以及CNS多巴胺能反应性与多巴胺能系统的两个基因调节元件的多态性相关：色氨酸羟化酶和单胺氧化酶A。拟议研究的目的是通过更明确的方法确认和扩展这些观察结果，利用以家庭为基础的对照，结合对成人、社区志愿者及其父母的传播不平衡（TDT）分析。主要研究样本将包括800名个体，包括通过标准化临床访谈评估的侵袭性表型群体分布的相对末端（四分位数）。还将评估多巴胺能系统中的其他多态性，如果发现非功能性多态性的等位基因可区分高和低侵袭性受试者，则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。将通过结构化诊断评估对研究参与者进行精神病学表征，并通过额外的访谈、问卷调查和对抗性倾向和冲动的观察指标确认攻击行为的组间差异。该项目的发现将促进对人类气质的一个重要维度的遗传相关性的理解，该维度与反社会行为、暴力、人际关系困扰和个性相关的精神病理学密切相关。本申请书是先前同一标题提案的重新提交。

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.