Neurogenetics Lab Scan Suggests Genetic Linkage on
Chromosomes 4 and 11

Washington, D.C. Jeffrey C. Long, Ph.D., David Goldman, M.D., and coworkers in the Laboratory of Neurogenetics, Division of Intramural Clinical and Biological Research, NIAAA, report in this month's Neuropsychiatric Genetics(Volume 81, Number 3) highly suggestive evidence in one region of chromosome 11 and good evidence in one region of chromosome 4 for linkage to alcohol dependence (commonly termed alcoholism) risk. Consistent with findings from an independent NIAAA-supported genome scan reported in the same journal issue, the researchers also identified a chromosome 4 region near the alcohol dehydrogenase (ADH) gene cluster as suggestive for linkage to alcoholism resistance.

"That independent genome scans in quite different populations suggest linkage in the same region sparks the search for human genes that enhance or reduce alcoholism risk," said NIAAA Director Enoch Gordis, M.D. The human gene search has been a principal research priority under Dr. Gordis' leadership. "Especially because alcoholism involves the interaction of multiple genes and environmental factors that can differ among ethnic groups, families, and even individuals within a family, progress to this point is impressive. The logical next step is conclusive evidence for linkage, followed by high- resolution mapping to determine which of the hundreds of genes in this region are protective," he said.

Dr. Long and laboratory chief David Goldman, M.D., described a finding on the distal short arm of chromosome 11 as most striking in their southwest American Indian population. Genes implicated in neurotransmission previously have been identified on a short arm of chromosome 11, including the DRD4 dopamine receptor gene recently associated with novelty-seeking in Israelis and Euroamericans. Also on the short arm of chromosome 11 are the tyrosine hydroxylase gene involved in dopamine biosynthesis, and the tryptophan hydroxylase gene involved in serotonin biosynthesis. With other brain neurotransmitter systems, dopamine and serotonin long have been implicated in alcoholism, in particular relation to alcohol's rewarding effects and the reinforcement of drinking behavior.

"From the early work of former Scientific Director Markku Linnoila, M.D., Ph.D., to recent studies by this laboratory in alcohol dependent Finnish men, serotonin has recurred as a prime suspect in severe alcoholism," Dr. Goldman said.

The Neurogenetics laboratory for some years has studied genetically and environmentally homogenous population isolates using a combination of whole genome linkage and direct analysis of candidate genes. Well-defined groups such as American Indian tribes provide unique opportunities to identify common genetic and environmental influences on complex diseases such as alcoholism. The relatively reduced genetic and environmental variations in such populations make it easier to determine which genetic variants are co- inherited with alcoholism.

Together with high alcoholism prevalence, the 582 participants in the current study share a common heritage of biology, culture, language, and location that dates from pre-Columbian times. Because of high alcoholism prevalence, the researchers selected the study population without clinical assessment, on the basis of multigenerational genealogies, current family structure, geographic availability, and willingness to advocate for the study.

Of the 582 participants, the researchers clinically evaluated 152 comprising 172 sibling pairs from 32 interrelated nuclear families according to DSM-III-R* diagnostic criteria. The research team then examined genotypes at 517 autosomal microsatellite loci at an average interval of 6.9 centimorgans (cM) and applied advanced statistical methods to assess results across affected, unaffected, and discordant (one sibling with alcoholism and one without) sibling pair groups.

According to Dr. Long, "A finding the strength of ours on chromosome 11 would occur by chance for only 1 in 6 whole-genome scans on a perfect genetic map and only 1 in 33 scans using markers at intervals of 10 cM." The chromosome 11 finding thus is highly suggestive but will require replication to be called definitive.

A region on chromosome 4 near a gamma-aminobutyric acid (GABA) receptor gene cluster also provided suggestive evidence for linkage to alcoholism risk. Ethanol is known to enhance GABA receptor actions, an effect believed to influence intoxication, tolerance, withdrawal severity, and cognitive effects of alcohol consumption, and researchers long have suspected that variant forms of GABA receptor genes may contribute to alcoholism vulnerability. To determine whether this GABA receptor gene is responsible for the chromosome 4 linkage finding, high resolution mapping will be required.

Like the Collaborative Study on the Genetics of Alcoholism scan in predominantly Caucasian families, Dr. Long and his colleagues identified a second region on chromosome 4 near the alcohol dehydrogenase (ADH) gene cluster as suggestive of linkage to alcoholism resistance. One of two principal enzymes involved in alcohol metabolism, ADH catalyzes the conversion of alcohol to acetaldehyde. High ADH activity produces excessive acetaldehyde, which can cause uncomfortable facial flushing, diminish tolerance, and thereby prevent drinking that might lead to alcohol dependence. (Deficient activity by a second alcohol- metabolizing enzyme, aldehyde dehydrogenase, similarly produces excess acetaldehyde and aversive symptoms in many persons of Asian descent.) Although, in the American Indian scan, the chromosome 4 finding was not supported across all analyses, ongoing research in this population is likely to reveal protective factors additional to those derived from ADH, the authors said.

To schedule interviews with Drs. Long and Goldman, telephone the NIAAA press office (301/443-3860). For additional information on alcoholism genetics 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 country's lead agency for biomedical and behavioral health research.

* American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (1987) and Feighner, J.P. Diagnostic Criteria for Use in Psychiatric Research (1972).

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