Search

Evidence suggests the P3 amplitude of the event-related potential and its underlying superimposed event-related oscillations (EROs), primarily in the theta (4-5 Hz) and delta (1-3 Hz) frequencies, as endophenotypes for the risk of alcoholism and other disinhibitory disorders. Major neurochemical substrates contributing to theta and delta rhythms and P3 involve strong GABAergic, cholinergic and glutamatergic system interactions. The aim of this study was to test the potential associations between single nucleotide polymorphisms (SNPs) in glutamate receptor genes and ERO quantitative traits. GRM8 was selected because it maps at chromosome 7q31.3-q32.1 under the peak region where we previously identified significant linkage (peak LOD = 3.5) using a genome-wide linkage scan of the same phenotype (event-related theta band for the target visual stimuli). Neural activities recorded from scalp electrodes during a visual oddball task in which rare target elicited P3s were analyzed in a subset of the Collaborative Study on the Genetics of Alcoholism (COGA) sample comprising 1,049 Caucasian subjects from 209 families (with 472 DSM-IV alcohol dependent individuals). The family-based association test (FBAT) detected significant association (P < 0.05) with multiple SNPs in the GRM8 gene and event-related theta power to target visual stimuli, and also with alcohol dependence, even after correction for multiple comparisons by false discovery rate (FDR). Our results suggest that variation in GRM8 may be involved in modulating event-related theta oscillations during information processing and also in vulnerability to alcoholism. These findings underscore the utility of electrophysiology and the endophenotype approach in the genetic study of psychiatric disorders., ((c) 2008 Wiley-Liss, Inc.)

Brain oscillations provide a rich source of potentially useful endophenotypes (intermediate phenotypes) for psychiatric genetics, as they represent important correlates of human information processing and are associated with fundamental processes from perception to cognition. These oscillations are highly heritable, are modulated by genes controlling neurotransmitters in the brain, and provide links to associative and integrative brain functions. These endophenotypes represent traits that are less complex and more proximal to gene function than either diagnostic labels or traditional cognitive measures, providing a powerful strategy in searching for genes in psychiatric disorders. These intermediate phenotypes identify both affected and unaffected members of an affected family, including offspring at risk, providing a more direct connection with underlying biological vulnerability. Our group has utilized heritable neurophysiological features (i.e., brain oscillations) as endophenotypes, making it possible to identify susceptibility genes that may be difficult to detect with diagnosis alone. We have discussed our findings of significant linkage and association between brain oscillations and genes in GABAergic, cholinergic and glutamatergic systems (GABRA2, CHRM2, and GRM8). We have also shown that some oscillatory indices from both resting and active cognitive states have revealed a common subset of genetic foci that are shared with the diagnosis of alcoholism and related disorders. Implications of our findings have been discussed in the context of physiological and pharmacological studies on receptor function. These findings underscore the utility of quantitative neurophysiological endophenotypes in the study of the genetics of brain function and the genetic diathesis underlying complex psychiatric disorders.

Event-related oscillations (EROs) have proved to be very useful in the understanding of a variety of neurocognitive processes including reward/outcome processing. In the present study, theta power (4.0-7.0 Hz) following outcome stimuli in the time window of the N2-P3 complex (200-500 ms) was analyzed in healthy normals (20 males and 20 females) while performing a gambling task that involved monetary loss and gain. The main aim was to analyze outcome processing in terms of event-related theta power in the context of valence, amount, gender, and impulsivity. The S-transform was used for the signal processing of the ERO data in terms of time-frequency-power. Results from filtered waveforms showed a partially consistent phase-alignment of the increased theta activity corresponding to N2 and P3 components following the outcome stimuli. Gain conditions produced more theta power than loss conditions. While there was anterior involvement in both gain and loss, posterior activation was stronger during gain conditions than during loss conditions. Females exhibited posterior maxima during gain conditions while males had an anterior maxima during both loss and gain conditions. The current source density of theta activity in females involved larger areas with a bilateral frontal activity while males predominantly had a frontal midline activity. Theta power was significantly higher in females than males across all conditions. Low theta (4.0-5.5 Hz) predominantly contributed to the posterior activity during gain conditions. High theta (5.5-7.0 Hz) was more associated with impulsivity measures than low theta activity. These findings may offer valuable clues to understand outcome processing, impulsivity, and gender differences.

Biological endophenotypes are more proximal to gene function than psychiatric diagnosis, providing a powerful strategy in searching for genes in psychiatric disorders. These intermediate phenotypes identify both affected and unaffected members of an affected family, including offspring at risk, providing a more direct connection with underlying biological vulnerability. The Collaborative Study on the Genetics of Alcoholism (COGA) has employed heritable neurophysiological features (i.e., brain oscillations) as endophenotypes, making it possible to identify susceptibility genes that may be difficult to detect with diagnosis alone. We found significant linkage and association between brain oscillations and genes involved with inhibitory neural networks (e.g., GABRA2, CHRM2), including frontal networks that are deficient in individuals with alcohol dependence, impulsivity, and related disinhibitory disorders. We reported significant linkage and linkage disequilibrium for the beta frequency of the EEG and GABRA2, a GABAA receptor gene on chromosome 4, which we found is also associated with diagnosis of alcohol dependence and related disorders. More recently, we found significant linkage and association with GABRA2 and interhemispheric theta coherence. We also reported significant linkage and linkage disequilibrium between the theta and delta event-related oscillations underlying P3 to target stimuli and CHRM2, a cholinergic muscarinic receptor gene on chromosome 7, which we found is also associated with diagnosis of alcohol dependence and related disorders. Thus, the identification of genes important for the expression of the endophenotypes (brain oscillations) helps when identifying genes that increase the susceptibility for risk of alcohol dependence and related disorders. These findings underscore the utility of quantitative neurophysiological endophenotypes in the study of the genetics of complex disorders. We will present our recent genetic findings related to brain oscillations and Central Nervous System (CNS) disinhibition.

The additive genetic heritability of bipolar EEG coherence in a sample of 305 non-twin sibships comprising 690 individuals (age range 7-65) was estimated. Heritabilities were examined in 6 frequency bands for each of 15 coherence pairs, both interhemispheric and intrahemispheric. The heritabilities of the bipolar EEG coherence ranged from 0.22 to 0.63 in 79 of the 90 phenotypes which had coherences high enough to provide meaningful values for the estimation of heritability. Heritabilities were greatest in the low and high alpha frequency bands, while theta and beta bands had comparable heritabilities. Coherences themselves were greatest in the low and high alpha frequency bands, while theta coherences were somewhat larger than beta. Higher heritability values were not associated with higher coherences. The examination of bivariate genetic correlations suggests that there is a difference between theta and alpha bands in genetic control of interhemispheric coherence.

Subtle cognitive deficits can be studied using event-related potentials (ERP), brain waves elicited in response to sensory stimuli. ERP studies suggest that certain memory processes are impaired in alcoholics; therefore, each incoming stimulus must be evaluated anew. Some ERP anomalies occur in nonalcoholic subjects from alcoholic families, indicating that these anomalies may antecede the development of alcoholism.