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

Introduction to the Special Issue: Human Linkage Studies for Behavioral Traits

In the post Genome era, the aim of behavior genetics has shifted from estimating the relative contributions of genes and environmental factors to (co-)variation in human complex traits, to localization of genes and identification of functional genetic variants. This special issue reflects this transition and presents fifteen papers that report on genome-wide linkage scans for complex traits in humans and on methodological tools and innovations. Six papers focus on cognition and report overlapping linkage peaks on chromosomes 6p and 14p. Papers on addictive behavior, i.e. smoking and alcohol dependence and its endophenotypes, find moderate LOD scores on chromosomes 6p, 5q, 4p and 7q, respectively. Three papers concentrate on emotionality, depression and loneliness and examine chromosomes 2q and 12q. The papers in this issue represent a summary of the first large scale linkage enterprises of human behavioral traits. © 2006 Springer Science+Business Media, Inc.link_to_subscribed_fulltex

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

Genetic contribution to the P3 in young and middle-aged adults.

Previous studies in young and adolescent twins suggested substantial genetic contributions to the amplitude and latency of the P3 evoked by targets in an oddball paradigm. Here we examined whether these findings can be generalized to adult samples. A total of 651 twins and siblings from 292 families participated in a visual oddball task. In half of the subjects the age centered around 26 (young adult cohort), in the other half the age centered around 49 (middle-aged adult cohort). P3 peak amplitude and latency were scored for 3 midline leads Pz, Cz, and Fz. No cohort differences in heritability were found. P3 amplitude (∼50%) and latency (∼45%) were moderately heritable for the 3 leads. A single genetic factor influenced latency at all electrodes, suggesting a single P3 timing mechanism. Specific genetic factors influenced amplitude at each lead, suggesting local modulation of the P3 once triggered. Genetic analysis of the full event-related potential waveform showed that P3 heritability barely changes from about 100 ms before to 100 ms after the peak. Age differences are restricted to differences in means and variances, but the proportion of genetic variance as part of the total variance of midline P3 amplitude and latency does not change from young to middle-aged adulthood

ADH1B is associated with alcohol dependence and alcohol consumption in populations of European and African ancestry.

A coding variant in alcohol dehydrogenase 1B (ADH1B) (rs1229984) that leads to the replacement of Arg48 with His48 is common in Asian populations and reduces their risk for alcoholism, but because of very low allele frequencies the effects in European or African populations have been difficult to detect. We genotyped and analyzed this variant in three large European and African-American case-control studies in which alcohol dependence was defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, and demonstrated a strong protective effect of the His48 variant (odds ratio (OR) 0.34, 95% confidence interval (CI) 0.24, 0.48) on alcohol dependence, with genome-wide significance (6.6 × 10(-10)). The hypothesized mechanism of action involves an increased aversive reaction to alcohol; in keeping with this hypothesis, the same allele is strongly associated with a lower maximum number of drinks in a 24-hour period (lifetime), with P=3 × 10(-13). We also tested the effects of this allele on the development of alcoholism in adolescents and young adults, and demonstrated a significantly protective effect. This variant has the strongest effect on risk for alcohol dependence compared with any other tested variant in European populations

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

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