March 12, 2002 -- Bernice Porjesz, Ph.D., Department of Psychiatry, State University of New York, Health Sciences Center at Brooklyn, and others from six of the nine universities that comprise NIAAA's Collaborative Study of the Genetics of Alcoholism (COGA) report in today's online version of the Proceedings of the National Academy of Sciences (99:3729-3733) significant linkage and linkage disequilibrium between beta brain wave (EEG) frequency and a cluster of gamma-aminobutyric acid type A (GABAA) receptor genes on human chromosome 4. Conducted in the laboratory of COGA Principal Investigator Dr. Henri Begleiter, the study is coauthored by Laura Almasy, Ph.D., Howard J. Edenberg, Ph.D., and Theodore Reich, Ph.D., among others.
"Drs. Porjesz and Begleiter are the first to find a specific genetic locus associated with fundamental human brain oscillations. Their work contributes to understanding of brain neuroelectric activity and expedites our search for alcoholism risk and protective genes," said NIAAA Acting Director Raynard S. Kington, M.D., Ph.D.
Since the 1929 discovery of the human electroencephalogram (EEG), scientists have measured brain electrical activity, displayed as undulating lines with "peaks" and "valleys" called waves. Oscillations in these waves represent important features of information processing and are highly heritable. Beta EEG frequency, elevated in alcoholics and their alcohol-naïve offspring, for some years has been regarded as a possible marker of alcoholism susceptibility. While its specific functional role is not yet defined, beta wave oscillation reflects heightened activity of the underlying neuronal network, scientists believe.
Activity of GABAA, the primary receptor subtype of the inhibitory brain neurotransmitter GABA, is responsible for nerve cell inhibition throughout the brain. Mounting evidence from human and animal studies implicates GABAA in the development of tolerance to and dependence on alcohol and in genetic liability for alcoholism. Among its many functions, GABAA serves as the gatekeeper for neurons that influence beta EEG frequency. Scientists have speculated that some perturbation of GABAA activity is responsible for heightened beta EEG activity in alcoholics and their offspring.
The authors of today's study relied on recent advances in statistical and molecular genetics that permit scientists to examine neurobiological phenotypes in conjunction with DNA markers. They examined beta EEG frequency and DNA markers in a sample of 1553 individuals drawn from a COGA sample of 250 alcoholism-affected families and found the strongest evidence for linkage with EEG power on the short-arm of chromosome 4 for the beta traits. Their results provide strong evidence for an association between beta EEG frequencies and a cluster of genes located on chromosome 4.
In 1998, COGA identified a "hot spot" for a possible alcoholism-related gene on chromosome 4 from a whole-genome scan of families with high alcoholism prevalence. At the same time, NIAAA's Laboratory of Neurogenetics reported from independent scan evidence on chromosome 4 for both alcoholism-risk and alcoholism-protective gene loci. Subsequent replication studies have provided additional evidence suggestive of alcohol-related genes in a specific area of chromosome 4.
Full text of the paper appears at 5:00 p.m. in the PNAS Early Edition at http://www.pnas.org.
The National Institute on Alcohol Abuse and Alcoholism, a component of the National Institutes of Health, U.S. Department of Health and Human Services, conducts and supports approximately 90 percent of U.S. research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems and disseminates research findings to science, practitioner, policy making, and general audiences.
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