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The Dopamine D2 Receptor Locus as a Modifying Gene in Neuropsychiatric Disorders
David E. Comings, MD;
Brenda G. Comings, PhD;
Donn Muhleman, MS;
George Dietz, PhD;
Bejan Shahbahrami, MS;
David Tast;
Ellen Knell, PhD;
Pat Kocsis, LCSW;
Rubin Baumgarten;
Bruce W. Kovacs, MD;
Deborah L. Levy, PhD;
Melissa Smith, MA;
Richard L. Borison, MD, PhD;
D. Durrell Evans, MD;
Daniel N. Klein, PhD;
James MacMurray, PhD;
Jeffrey M. Tosk, PhD;
Jeffrey Sverd, MD;
Reinhard Gysin, PhD;
Steven D. Flanagan, PhD
JAMA. 1991;266(13):1793-1800.
Abstract
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Objective.
—The A1 allele of the Taq I polymorphism of the dopamine D2 receptor (DRD2) gene has been earlier reported to occur in 69% of alcoholics, compared with 20% of controls. Other research has reported no significant difference in the prevalence of the A1 allele in alcoholics vs controls and no evidence that the DRD2 gene was linked to alcoholism. We hypothesized that these seemingly conflicting results might be because increases in the prevalence of the A1 allele may not be specific to alcoholism. Thus, we examined other disorders frequently associated with alcoholism or those believed to involve defects in dopaminergic neurotransmission.
Design.
—Case comparison study. To minimize the effect of racial differences in gene frequencies, the study was restricted to non-Hispanic whites.
Setting.
—Ambulatory and hospitalized patients.
Results.
—Among all known controls (n = 314), 77 (24.5%) carried the A1 allele. Of the 69 controls known not to be alcoholics, 10 (14.5%) carried the A1 allele. The prevalence of the A1 allele was significantly increased in patients with Tourette's syndrome (44.9%, n = 147), attention deficit hyperactivity disorder (46.2%, n = 104), autism (54.5%, n = 33), alcoholism (42.3%, n = 104), and posttraumatic stress disorder (45.7%, n = 35). After correction for multiple comparisons (requiring P<.0009 for significance), all remained significant except posttraumatic stress disorder. The prevalence of the A1 allele was not significantly increased in patients with depression, panic attacks, Parkinson's disease, or obesity. The prevalence of the A1 allele in drug addiction and schizophrenia was only significant when compared with that of controls who were not alcoholics, and no correction was made for multiple comparisons.
Conclusion.
—These results suggest the A1 allele of the DRD2 gene is associated with a number of behavior disorders in which it may act as a modifying gene rather than as the primary etiological agent.
(JAMA. 1991;266:1793-1800)
Author Affiliations
From the Department of Medical Genetics (Drs D. Comings and B. Comings, Mr Muhleman, Dr Dietz, Messrs Shahbahrami and Tast, Dr Knell, Ms Kocsis, Mr Baumgarten, and Dr Kovacs), and the Division of Neurosciences, Beckman Research Institute (Drs Flanagan and Gysin), City of Hope National Medical Center, Duarte, Calif; Department of Research, McLean Hospital, Belmont, Mass (Dr Levy); Department of Psychiatry Research, Hillside Hospital, Glen Oaks, NY (Ms Smith); Department of Psychology, State University of New York at Stony Brook (Dr Klein); Department of Psychiatry, Jerry L. Pettis Veterans Administration Hospital, Loma Linda, Calif (Drs MacMurray and Tosk); Departments of Psychiatry, North Shore University Hospital and Cornell University Medical College, Manhasset, NY (Dr Sverd); Department of Psychiatry, Medical College of Georgia and Psychiatry Service, Veterans Administration Medical Center, Augusta, Ga (Drs Borison and Evans).
Footnotes
Reprint requests to Department of Medical Genetics, City of Hope National Medical Center, 1500 E Duarte Rd, Duarte, CA 91010-0269 (Dr D. Comings).
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