COGA Suggests Genetic LOCI for P3 Brain Wave Abnormaility
Washington, D.C. Drs. Henri Begleiter and Bernice Porjesz, Department of Psychiatry, State University of New York Health Science Center at Brooklyn, and colleagues in the six-university Collaborative Study on the Genetics of Alcoholism (COGA) identify in the May
Electroencephalography and Clinical Neurophysiology (Volume 108, Number 3) chromosomal regions that may underlie the functional organization of human neuroelectric activity, including the event-related brain potential known as P3. Since the 1980s, when Dr. Begleiter first identified reduced P3 wave amplitude in alcohol-naive sons of alcoholics, researchers have regarded the abnormality as a potential noninvasive marker of genetic risk for alcoholism.
Event-related potentials (ERPs) are brain electrical signals produced in response to specific sensory stimuli (such as a light or a sound) that provide sensitive measures of cognitive activity. Measured at the scalp using standard electroencephalography (EEG) technology, ERPs are displayed as wave-like lines and measured according to their height (amplitude) and elapsed time following a stimulus. The P3 or P300 ERP component peaks between 300 and 500 milliseconds after a stimulus, and its amplitude is higher for significant than insignificant stimuli. Persons with low P3 amplitude are believed to have difficulty distinguishing significant from insignificant stimuli.
Previous studies repeatedly found P3 voltage to be low in several clinical conditions including schizophrenia, attention deficit disorder, and alcoholism. Although, with alcoholism, researchers initially attributed low P3 voltage to the cumulative toxic effects of alcohol, Drs. Begleiter and Porjesz in 1985 demonstrated that P3 remains low in alcoholics who have been abstinent for as long as 10 years. In 1991, another research team related low P3 amplitude to number of alcoholic first-degree relatives rather than personal drinking history. Such indications that low P3 amplitudes predate heavy drinking and might be inherited led COGA investigators at all sites to establish neurophysiology laboratories and collect ERP data from the dense alcoholic families and controls under study.
Genetic analysis involved 607 individuals from 103 families in whom the COGA investigators had tested P3 responses to a variety of visual stimuli. Researchers then performed a whole-genome screen using microsatellite markers at intervals of 14 centimorgans (cM) and genotyped study participants. For chromosomal regions of interest, they used multipoint linkage analysis to extract additional genetic information from the data, thereby increasing statistical significance of the findings. Results showed that in persons with high familial alcoholism, P3 amplitude statistically was reduced significantly compared with control families.
Genetic linkage analysis yielded significant evidence for linkage on chromosomes 2 and 6 and suggestive evidence on chromosomes 5 and 13. The chromosomal regions linked to P3 amplitude each contain several hundred genes including those encoding ionotropic glutamate receptors and two subunits of the acetylcholine receptor. Whether these genes are responsible for the observed genetic linkage remains to be determined by high-resolution mapping.
It is now well established that reduced P3 amplitude is associated with alcoholism risk. Drs. Begleiter and Porjesz currently are working to define the precise nature of that relationship. "Knowing the genes responsible for the P3 phenomenon should enhance understanding of brain neuroelectric activity in general, a contribution from alcohol research to cognitive and clinical neuroscience," said Dr. Begleiter. Dr. Begleiter has served as chairperson of COGA from its inception in 1989 to the present.
For interviews May 20-21, telephone the NIAAA press office. For interviews after May 21, telephone Dr. Begleiter at 718/270-2024. For additional information on the genetics of alcoholism and other areas of alcohol research, telephone NIAAA or visit
http://www.niaaa.nih.gov/.
NIAAA is one of 18 components of the National Institutes of Health, the nations lead agency for biomedical and behavioral health research.
Reference
Indiana University, University of Connecticut, University of California at San Diego, State University of New York- Health Science Center at Brooklyn, University of Iowa.