No Linkage Between D2 Dopamine Receptor Gene Region and Schizophrenia

Hans W. Moises, Joel Gelernter, Luis A. Giuffra, Vincent Zarcone, Lennart Wetterberg, Olivier Civelli, Kenneth K. Kidd, Luca L. Cavalli Sforza, David K. Grandy, James L. Kennedy, Sophia Vinogradov, John Mauer, Michael Litt, Barbro Sjögren

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

Abstract

• 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 D 2 dopamine receptor densities in untreated schizophrenic patients support the D 2 dopamine receptor gene as a strong candidate gene for schizophrenia. The recent cloning of the D 2 dopamine receptor gene made it possible to test the involvement of the D 2 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 D 2 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 D 2 dopamine receptor hypothesis of schizophrenia. However, they cannot exclude the possibility that other genes regulating aspects of D 2 dopamine expression might be involved in the etiology of schizophrenia, such as the expression of two D 2 dopamine receptor subtypes by alternative RNA splicing.

Original languageEnglish (US)
Pages (from-to)643-647
Number of pages5
JournalArchives of General Psychiatry
Volume48
Issue number7
DOIs
StatePublished - Jul 1991

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