Visual P3a in Male Subjects at High Risk for Alcoholism

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)S

Gender modulates the development of Theta Event Related Oscillations in Adolescents and Young Adults.

The developmental trajectories of theta band (4-7 Hz) event-related oscillations (EROs), a key neurophysiological constituent of the P3 response, were assessed in 2170 adolescents and young adults ages 12 to 25. The theta EROs occurring in the P3 response, important indicators of neurocognitive function, were elicited during the evaluation of task-relevant target stimuli in visual and auditory oddball tasks. These tasks call upon attentional and working memory resources. Large differences in developmental rates between males and females were found; scalp location and task modality (visual or auditory) differences within males and females were small compared to gender differences. Trajectories of interregional and intermodal correlations between ERO power values exhibited increases with age in both genders, but showed a divergence in development between auditory and visual systems during ages 16 to 21. These results are consistent with previous electrophysiological and imaging studies and provide additional temporal detail about the development of neurophysiological indices of cognitive activity. Since measures of the P3 response has been found to be a useful endophenotypes for the study of a number of clinical and behavioral disorders, studies of its development in adolescents and young adults may illuminate neurophysiological factors contributing to the onset of these conditions

Using Patterns of Genetic Association to Elucidate Shared Genetic Etiologies Across Psychiatric Disorders

Twin studies indicate that latent genetic factors overlap across comorbid psychiatric disorders. In this study, we used a novel approach to elucidate shared genetic factors across psychiatric outcomes by clustering single nucleotide polymorphisms based on their genome-wide association patterns. We applied latent profile analysis (LPA) to p-values resulting from genome-wide association studies across three phenotypes: symptom counts of alcohol dependence (AD), antisocial personality disorder (ASP), and major depression (MD), using the European–American case-control genome-wide association study subsample of the collaborative study on the genetics of alcoholism (N = 1399). In the 3-class model, classes were characterized by overall low associations (85.6% of SNPs), relatively stronger association only with MD (6.8%), and stronger associations with AD and ASP but not with MD (7.6%), respectively. These results parallel the genetic factor structure identified in twin studies. The findings suggest that applying LPA to association results across multiple disorders may be a promising approach to identify the specific genetic etiologies underlying shared genetic variance

Defining alcohol-related phenotypes in humans. The Collaborative Study on the Genetics of Alcoholism.

Alcoholism is a disease that runs in families and results at least in part from genetic risk factors. The Collaborative Study on the Genetics of Alcoholism (COGA) is a Federally funded effort to identify and characterize those genetic factors. The study involves more than 1,000 alcoholic subjects and their families, with researchers conducting comprehensive psychological, physiological, electrophysiological, and genetic analyses of the participants. These analyses have identified several traits, or phenotypes, that appear to be genetically determined, such as the presence of alcohol dependence, the level of response to alcohol, the presence of coexisting depression, or the maximum number of drinks a person consumes per occasion. Genetic analyses have identified regions on several chromosomes that are associated with these phenotypes and need to be studied further

The Impact of Peer Substance Use and Polygenic Risk on Trajectories of Heavy Episodic Drinking Across Adolescence and Emerging Adulthood

BACKGROUND: Heavy episodic drinking is developmentally normative among adolescents and young adults, but is linked to adverse consequences in later life, such as drug and alcohol dependence. Genetic and peer influences are robust predictors of heavy episodic drinking in youth, but little is known about the interplay between polygenic risk and peer influences as they impact developmental patterns of heavy episodic drinking. METHODS: Data were from a multisite prospective study of alcohol use among adolescents and young adults with genome-wide association data (n = 412). Generalized linear mixed models were used to characterize the initial status and slopes of heavy episodic drinking between age 15 and 28. Polygenic risk scores (PRS) were derived from a separate genome-wide association study for alcohol dependence and examined for their interaction with substance use among the adolescents' closest friends in predicting the initial status and slopes of heavy episodic drinking. RESULTS: Close friend substance use was a robust predictor of adolescent heavy episodic drinking, even after controlling for parental knowledge and peer substance use in the school. PRS were predictive of the initial status and early patterns of heavy episodic drinking in males, but not in females. No interaction was detected between PRS and close friend substance use for heavy episodic drinking trajectories in either males or females. CONCLUSIONS: Although substance use among close friends and genetic influences play an important role in predicting heavy episodic drinking trajectories, particularly during the late adolescent to early adult years, we found no evidence of interaction between these influences after controlling for other social processes, such as parental knowledge and broader substance use among other peers outside of close friends. The use of longitudinal models and accounting for multiple social influences may be crucial for future studies focused on uncovering gene-environment interplay. Clinical implications are also discussed

Genetic correlates of the development of theta event related oscillations in adolescents and young adults

The developmental trajectories of theta band (4–7 Hz) event-related oscillations (EROs), a key neurophysiological constituent of the P3 response, were assessed in 2170 adolescents and young adults ages 12 to 25. The theta EROs occurring in the P3 response, important indicators of neurocognitive function, were elicited during the evaluation of task-relevant target stimuli in visual and auditory oddball tasks. Associations between the theta EROs and genotypic variants of 4 KCNJ6 single nucleotide polymorphisms (SNPs) were found to vary with age, sex, scalp location, and task modality. Three of the four KCNJ6 SNPs studied here were found to be significantly associated with the same theta EROs in adults in a previous family genome wide association study. Since measures of the P3 response have been found to be a useful endophenotypes for the study of a number of clinical and behavioral disorders, studies of genetic effects on its development in adolescents and young adults may illuminate neurophysiological factors contributing to the onset of these conditions

Genetic and neurophysiological correlates of the age of onset of alcohol use disorders in adolescents and young adults.

Discrete time survival analysis was used to assess the age-specific association of event-related oscillations (EROs) and CHRM2 gene variants on the onset of regular alcohol use and alcohol dependence. The subjects were 2,938 adolescents and young adults ages 12-25. Results showed that the CHRM2 gene variants and ERO risk factors had hazards which varied considerably with age. The bulk of the significant age-specific associations occurred in those whose age of onset was under 16. These associations were concentrated in those subjects who at some time took an illicit drug. These results are consistent with studies which associate greater rates of alcohol dependence among those who begin drinking at an early age. The age specificity of the genetic and neurophysiological factors is consistent with recent studies of adolescent brain development, which locate an interval of heightened vulnerability to substance use disorders in the early to mid teens

Genome-wide survival analysis of age at onset of alcohol dependence in extended high-risk COGA families.

BackgroundThe age at onset of alcohol dependence (AD) is a critical moderator of genetic associations for alcohol dependence. The present study evaluated whether single nucleotide polymorphisms (SNPs) can influence the age at onset of AD in large high-risk families from the Collaborative Study on the Genetics of Alcoholism (COGA).MethodsGenomewide SNP genotyping was performed in 1788 regular drinkers from 118 large European American families densely affected with alcoholism. We used a genome-wide Cox proportional hazards regression model to test for association between age at onset of AD and SNPs.ResultsThis family-based analysis identified an intergenic SNP, rs2168784 on chromosome 3 that showed strong evidence of association (P=5×10(-9)) with age at onset of AD among regular drinkers. Carriers of the minor allele of rs2168784 had 1.5 times the hazard of AD onset as compared with those homozygous for the major allele. By the age of 20 years, nearly 30% of subjects homozygous for the minor allele were alcohol dependent while only 19% of those homozygous for the major allele were. We also identified intronic SNPs in the ADP-ribosylation factor like 15 (ARL15) gene on chromosome 5 (P=1.11×10(-8)) and the UTP20 small subunit (UTP20) gene on chromosome 12 (P=4.32×10(-8)) that were associated with age at onset of AD.ConclusionsThis extended family based genome-wide cox-proportional hazards analysis identified several loci that might be associated with age at onset of AD