Washington, D.C. Theodore Reich, M.D., Department of Psychiatry, Washington University School of Medicine, St. Louis,
and colleagues at that university and others* in the NIAAA-supported Collaborative Study on the Genetics of Alcoholism
(COGA) report in this month's Neuropsychiatric Genetics (Volume 81, Number 3) highly suggestive evidence on
chromosomes 1 and 7 and more modest evidence on chromosome 2 for linkage to alcohol dependence (commonly termed
alcoholism) vulnerability. Reporting from a whole-genome scan of families with high alcoholism prevalence, the researchers also
found evidence for linkage to a protective locus on chromosome 4 near the alcohol dehydrogenase (ADH) genes, a result
similar to that from an independent genome scan conducted by NIAAA's Laboratory of Neurogenetics and reported in the
same journal issue.
The COGA study assessed 987 individuals from 105 multigenerational families selected through 23 female and 82 male adults
in metropolitan inpatient and outpatient alcoholism treatment programs. Each of the 105 families contained at least three
first-degree relatives with alcohol dependence. Like alcoholics in the general U.S. population, the study group was
predominantly Caucasian and evidenced considerable comorbidity with other psychiatric diagnoses.
The researchers assessed participants according to DSM-III-R and Feighner diagnostic systems** operationalized through
the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) lifetime psychiatric interview designed for this study.
They then examined 291 DNA markers at an average interval of 13.8 centiMorgans using state-of-the-art statistical methods to
detect alcoholism susceptibility loci across affected, unaffected, and discordant (one affected and one unaffected) sibling pair
groups. While, by the strictest analytic criteria, no locus was definitive for linkage, loci on chromosomes 1, 2, 4, and 7 were of
sufficient strength to warrant further study.
"Highly suggestive evidence for linkage at one chromosome 1 locus was consistent across analytic methods and sibling pair
groups, strongly suggesting a gene in this region that is important in alcoholism susceptibility," said Dr. Reich. A second,
probably unrelated, chromosome 1 locus also evidenced involvement. Chromosome 7 evidence was strong in sibling pairs with
alcohol dependence but less well supported across all analytic methods, and the chromosome 2 finding modestly suggested
linkage according to stringent criteria.
The chromosome 4 evidence in unaffected sibling pairs suggests a protective locus near the region that contains the alcohol
dehydrogenase (ADH) gene cluster. ADH2 and ADH3 in that cluster are known to encode isozymes that accelerate the
metabolism of ethanol to acetaldehyde, creating the aversive "flushing reaction" that prevents many Asians from regular or
heavy drinking. Evidence for an additional protective chromosome 4 locus in COGA's predominantly Caucasian sample, taken
with that from an independent scan in an American Indian population, is the most potent to date from human alcoholism genetics
Alcoholism may be the most complex of the complex disorders, involving multiple genes and multiple neurotransmitter systems
that can differ from one family, even one individual, to the next, NIAAA Director Enoch Gordis, M.D. told reporters at a
National Press Club briefing held today. The briefing covered initial scientific publications from COGA, directed during the past
9 years by Dr. Henri Begleiter, State University of New York, Health Sciences Center at Brooklyn, and the latest publication
from NIAAA's Laboratory of Neurogenetics, directed by Dr. David Goldman. The two-track search for human alcoholism
genes has been a major NIAAA research priority under Dr. Gordis' leadership.
"When, over the next few years, we pinpoint the actual genes that confer and mitigate alcoholism risk, we can target preventive
interventions and devise pharmacologic treatments based on that knowledge. Understanding genetic factors also is the first
critical step in unraveling the more complex contribution of environmental factors," said Dr. Gordis.
COGA's first reports are a milestone in the most ambitious and authoritative genetics program ever mounted to study a
complex disorder, said Dr. Begleiter. "When in 1999 the data set becomes available to all qualified scientists, it will serve as a
COGA investigators now are analyzing results from a second scan in a similarly ascertained replication sample with 157 families
and 1313 informative members. For linkages confirmed by the replication, investigators will use flanking markers to narrow the
region of interest on each chromosome. "We also plan a 5-year prospective followup with juvenile members of the genotyped
families. Observing their development will allow us to directly measure the effects of susceptibility loci and to test
gene-environment hypotheses," Dr. Reich said.
To schedule May 20-21 interviews with Drs. Reich, Begleiter, and Gordis, telephone NIAAA (301/443-3860). After May
21, telephone Dr.Reich at 314/362-2149 and Dr. Begleiter at 718/270-2024.
For additional information on alcoholism genetics and other alcohol research subjects, visit http://www.niaaa.nih.gov. NIAAA
is one 18 components of the National Institutes of Health, the country's lead agency for biomedical and behavioral health
* Indiana University, University of Connecticut, University of California at San Diego, State University of New York - Health
Sciences Center at Brooklyn, University of Iowa
** 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). A close approximation to 1992
DSM- IV and ICD-10 criteria allowed comparisons with current diagnostic systems.