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Background: Voltage of the P300 component of eventrelated potentials (ERPs) has been proposed as a phenotypic marker of risk for alcoholism. P3a elicited by intrusive events is important in the context of deficits in inhibition found during psychophysiological and behavioral evaluations in children of alcoholics. Methods: ERPs were recorded from a group of adult children of alcoholics (n 5 26) and controls (n 5 23) with a three-stimulus visual oddball paradigm. The task required a difficult perceptual discrimination between a frequent (.80) vertical line and an infrequent (.10) 2° tilted line (target). An easily discriminable nontarget infrequent horizontal line also occurred (.10). Subjects were required to press a button to the target. P3a was compared using mixed-model ANCOVAs at 31 sites organized in 5 scalp regions. Current source density (CSD) maps were also analyzed. Results: High-risk (HR) subjects manifested reduced P3a amplitudes compared to controls at frontal, central, parietal, and temporal electrodes. CSD analyses supported these findings with group differences found for all the scalp regions. Conclusions: The results are discussed in relation to previous HR studies. P3a reductions may be related to deficits in neuronal inhibition during stimulus processing. These results suggest that P3a amplitude may be important as a marker for vulnerability to alcoholism. ; This research was supported by NIH Grants AA08401 and AA08403. Dr. Holguin is a Visiting Research Fellow at the Department of Psychiatry, State University of New York Health Science Center, supported by the Galician Government Research Authority (DOG 08/26/1997) ; SI

Context: The detection and replication of genes involved in psychiatric outcome has been notoriously difficult. Phenotypic measurement has been offered as one explanation, although most of this discussion has focused on problems with binary diagnoses. Objective: This article focuses on two additional components of phenotypic measurement that deserve further consideration in evaluating genetic associations: (1) the measure used to reflect the outcome of interest, and (2) the developmental stage of the study population. We focus our discussion of these issues around the construct of impulsivity and externalizing disorders, and the association of these measures with a specific gene, GABRA2. Design, Setting, and Participants: Data were analyzed from the Collaborative Study on the Genetics of Alcoholism Phase IV assessment of adolescents and young adults (ages 12–26; N = 2,128). Main Outcome Measures: Alcohol dependence, illicit drug dependence, childhood conduct disorder, and adult antisocial personality disorder symptoms were measured by psychiatric interview; Achenbach youth/adult self-report externalizing scale; Zuckerman Sensation-Seeking scale; Barratt Impulsivity scale; NEO extraversion and consciousness. Results: GABRA2 was associated with subclinical levels of externalizing behavior as measured by the Achenbach in both the adolescent and young adult samples. Contrary to previous associations in adult samples, it was not associated with clinical-level DSM symptom counts of any externalizing disorders in these younger samples. There was also association with sensation-seeking and extraversion, but only in the adolescent sample. There was no association with the Barratt impulsivity scale or conscientiousness. Conclusions: Our results suggest that the pathway by which GABRA2 initially confers risk for eventual alcohol problems begins with a predisposition to sensation-seeking early in adolescence. The findings support the heterogeneous nature of impulsivity and demonstrate that both the measure used to assess a construct of interest and the age of the participants can have profound implications for the detection of genetic associations.