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July 1991

No Linkage Between D2 Dopamine Receptor Gene Region and Schizophrenia

Author Affiliations

From the Departments of Genetics (Drs Moises and Cavalli Sforza) and Psychiatry (Drs Zarcone, Mauer, and Vinogradov), Stanford (Calif) University School of Medicine; the Department of Human Genetics, Yale University School of Medicine, New Haven, Conn (Drs Gelernter, Giuffra, Kidd, and Kennedy); the Vollum Institute for Advanced Biomedical Research, Oregon Health Sciences University, Portland (Drs Grandy, Civelli, and Litt); and the Department of Psychiatry, Karolinska Institute, Stockholm, Sweden (Dr Wetterberg and Ms Sjögren). Dr Moises is now with Kiel University Hospital, Kiel, Federal Republic of Germany. Dr Kennedy is a National Alliance for Research on Schizophrenia and Depression fellow.

Arch Gen Psychiatry. 1991;48(7):643-647. doi:10.1001/archpsyc.1991.01810310061011

• The dopamine hypothesis is one of the major etiological hypotheses of schizophrenia. The well-established role of genetic factors in schizophrenia together with reports of increased D2 dopamine receptor densities in untreated schizophrenic patients support the D2 dopamine receptor gene as a strong candidate gene for schizophrenia. The recent cloning of the D2 dopamine receptor gene made it possible to test the involvement of the D2 dopamine receptor locus (DRD2) in a large Swedish and a smaller Californian schizophrenia pedigree. Using multipoint linkage analysis between schizophrenia and a genetic map that includes the DRD2 locus and assuming a dominant mode of inheritance, we were able to exclude the DRD2 locus with a lod score of — 4.14 for the penetrance of 0.72 and with a lod score of — 3.05 for the lower bound penetrance of O.56. The area of exclusion (lod score, < — 2.00) extended 27 centimorgans. These results provide strong evidence against linkage of the D2 dopamine receptor gene region to schizophrenia in the two pedigrees investigated. We conclude that the genetic predisposition to schizophrenia in these pedigrees is not due to aberrations in the DRD2 locus or the porphobilinogen deaminase locus. Our results do not support the D2 dopamine receptor hypothesis of schizophrenia. However, they cannot exclude the possibility that other genes regulating aspects of D2 dopamine expression might be involved in the etiology of schizophrenia, such as the expression of two D2 dopamine receptor subtypes by alternative RNA splicing.

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