COGA Genome Scan Suggests Linkage On Chromosomes 1,2,4, And 7

May 20, 1998

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 studies.

 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 national resource."

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 NIAAA is one 18 components of the National Institutes of Health, the country's lead agency for biomedical and behavioral health research.

* 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.

NIH/National Institute on Alcohol Abuse and Alcoholism

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