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.