Yoon, H.H., Iacono, W.G., Malone, S.M. & McGue, M. (2006) Using the Brian P300 Response to Identify Novel Phenotypes Reflecting Genetic Vulnerability for Adolescent Substance Misuse. Addictive Behaviors, 31, 1067-1087.
We used a novel approach to identify candidate alternative phenotypes for investigating genetic influence underlying substance use disorders (SUDs) in adolescents. The existing literature suggests that P300 amplitude reduction (P3-AR) observed in brain event-related potentials is associated with risk for SUDs generally, not just alcoholism. Using data from a community-based sample of 17-year-old male and female twins, we fit biometric models to P3 amplitude data to show that it is strongly heritable, especially in boys. The extant evidence coupled with our findings strongly supports treating P3-AR as an endophenotype indexing SUD risk. We then examined a set of 15 potential alternative phenotypes (e.g., frequent use of cannabis) to determine whether they were associated with P3-AR. The results indicated that almost all of these alternative phenotypes were associated with P3-AR, with larger effect sizes observed for boys. Given the strong association of these use phenotypes with P3-AR, which is itself an index of genetic risk for SUDs, we conclude that these use phenotypes may provide tools for finding vulnerability genes in adolescents who have yet to pass through the age of risk for SUDs.
© 2006 Elsevier Ltd. All rights reserved.

Carlson, S.R., Iacono, W.G. & McGue, M. (2004) P300 Amplitude in Non-Alcoholic Adolescent Twin Pairs Who Become Discordant for Alcoholism as Adults. Psychophysiology, 41, 841-844.

Past reports suggest that reduced P300 amplitude is associated with risk for alcoholism. We examined whether visual P300 amplitude could identify familial risk for alcohol disorders in individuals not known to be at risk at the time P300 was recorded. These individualswere twins from pairswhere neither twin had an alcohol disorder at age 17 but familial risk was established at age 20 when one twin developed an alcohol disorder whereas the other did not. Of special interest was the P300 of the unaffected twin recorded at age 17 when both twins were alcoholism free. We found reduced P300 in the unaffected twin compared to pairs where both members were continuously disorder free. Hence, P300 was reduced in alcohol disorder-free individuals whose twin siblings subsequently developed alcoholism, further supporting reduced P300 amplitude as an endophenotype indexing familial risk for alcoholism.

Iacono, W.G., Malone, S & McGue, M. (2003). Substance Use Disorders, Externalizing Psychopathologies, and P300 Event Related Potential Amplitude. International Journal of Psychophysiology, 48, 147-178.
We hypothesize the existence of an inherited predisposition for a spectrum of behaviors and traits characterized by behavioral disinhibition. This externalizing spectrum includes childhood disruptive disorders, antisocial behavior, substance use disorders, personality traits related to behavioral under control, and the precocious expression of problem behavior. We further hypothesize that a genetically influenced central nervous system diathesis underlies this spectrum and is reflected in reduced P300 amplitude in a visual oddball event-related potential task. A review of evidence bearing on the model is derived from findings from the Minnesota Twin Family Study, a population-based, longitudinal investigation of twin youth. These findings indicate that the collection of attributes related to behavioral disinhibition is familial, heritable, and interrelated. Evidence supporting P3 amplitude reduction (P3-AR) as an index of genetic vulnerability for this externalizing spectrum includes its association with (a) familial risk for substance use and antisocial personality disorders, (b) diagnoses of childhood disruptive disorders and substance use disorders, (c) early onset of undersocialized behavior, and (d) quantitative phenotypes related to externalizing problems. In addition, the development of substance use disorders over a 3-year period is associated with P3-AR measured prior to their expression. These findings suggest that P3-AR indexes one aspect of the genetic diathesis for a spectrum of externalizing problem behavior.

Carlson, S.R., Iacono, W.G., & McGue, M. (2002). P300 Amplitude in Adolescent Twins Discordant for Alcohol Use Disorders. Biological Psychology, 61, 203-227.
The sons of alcoholics have repeatedly been found to have reduced P300 amplitude. Further, quantitative behavioral genetic and molecular genetic studies indicating a genetic influence on P300 amplitude have fueled speculation that this component may be a biological vulnerability marker for alcoholism. To further explore this possibility, we examined P300 in adolescent twin pairs from an epidemiological sample who were (a) discordant for alcohol abuse/dependence, (b) concordant for alcohol abuse/dependence, or (c) concordant for the absence of alcohol abuse/dependence and other relevant disorders. For discordant pairs, the alcohol abusing/dependent twins’ amplitude did not differ from that of non-alcoholic cotwins. Pairs free of psychopathology had greater amplitudes than both alcoholism discordant and concordant pairs. P300 amplitude was more similar in monozygotic than dizygotic discordant pairs, suggesting a genetic influence on P300 amplitude in this group. The findings are consistent with P300 amplitude being a marker of vulnerability to alcohol use disorders.

Katsanis, J., J. Taylor, et al. (2000). "Heritability of different measures of smooth pursuit eye tracking dysfunction: A study of normal twins." Psychophysiology 37, 724-730.

Taylor, J., S. R. Carlson, et al. (1999). "Individual differences in electrodermal responsivity to predictable aversive stimuli and substance dependence." Psychophysiology 36(2): 193-8.
To determine if the inability to take advantage of the predictability of an aversive stimulus to diminish its psychological impact reflects a deficit in inhibitory control related to the development of substance dependence, we recorded skin conductance responses (SCRs), heart rate (HR), and anticipatory electrodermal nonspecific fluctuations (NSFs) from 175 16-18-year-old boys when a white noise blast was either unpredictable or temporally predictable. Compared with boys who had moderately reduced or augmented SCRs to predictable blasts (moderate and poor modulators, respectively), boys whose SCRs were greatly reduced (good modulators) had fewer symptoms of alcohol and nicotine dependence and more anticipatory NSFs. HR appeared to index an active coping response for good and moderate modulators. The autonomic response pattern evident for good modulators may index an inhibitory control mechanism protecting them from developing substance dependence.

Iacono, W. G. (1998). "Identifying psychophysiological risk for psychopathology: examples from substance abuse and schizophrenia research." Psychophysiology 35(6): 621-37.
A problem confronting the search for psychopathology-related genes concerns the difficulty identifying gene carriers. Psychiatric diagnosis provides imperfect identification of affected individuals, and unaffected gene carriers go undetected. Psychophysiological measures may assist molecular genetic investigations by indicating genetic susceptibility for psychopathology, thus increasing the probability of identifying affected and unaffected gene carriers. Research strategies based on these premises are applied to the study of psychoactive substance use disorders and schizophrenia. Data are presented illustrating (1) that individual differences in inhibitory control involving autonomic and antisaccade eye movement measures and the P3 component of the event-related potential may be sensitive to susceptibility for substance use disorders, and (2) that eye tracking variables may identify genetic risk for schizophrenia.

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