This Article  • References  • Full text PDF  • Correction  • Reply to article  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Contact me when this article is cited  Related Content  • Similar articles in this journal  Social Bookmarking   What's this?

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

Arch Gen Psychiatry. 1991;48(7):643-647.

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 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.

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.

Footnotes
Accepted for publication October 24, 1990.

Reprint requests to Molecular Genetics Laboratory, Department of Psychiatry, University Hospital Kiel, Niemannsweg 147, D-2300 Kiel 1, Federal Republic of Germany (Dr Moises).

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter     What's this?

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Dopamine Receptors: From Structure to Function
MISSALE et al.
Physiol. Rev. 1998;78:189-225.
ABSTRACT | FULL TEXT  

Allelic Variation in the D4 Dopamine Receptor (DRD4) Gene Does Not Predict Response to Clozapine
Rao et al.
Arch Gen Psychiatry 1994;51:912-917.
ABSTRACT  

D2 Dopamine Receptor Alleles Do Not Influence Severity of Tourette's Syndrome: Results From Four Large Kindreds
Gelernter et al.
Arch Neurol 1994;51:397-400.
ABSTRACT  

Analysis of the D4 Dopamine Receptor Gene Variant in an Italian Schizophrenia Kindred
Macciardi et al.
Arch Gen Psychiatry 1994;51:288-293.
ABSTRACT  

No Structural Mutation in the Dopamine D2 Receptor Gene in Alcoholism or Schizophrenia: Analysis Using Denaturing Gradient Gel Electrophoresis
Gejman et al.
JAMA 1994;271:204-208.
ABSTRACT  

Schizophrenia as a Brain Disease: The Dopamine Receptor Story
Seeman
Arch Neurol 1993;50:1093-1095.
ABSTRACT  

Schizophrenia as a Brain Disease
Williamson
Arch Neurol 1993;50:1096-1097.
ABSTRACT  

Exclusion of Linkage Between Schizophrenia and the D2 Dopamine Receptor Gene Region of Chromosome 11q in 112 Irish Multiplex Families
Su Ying et al.
Arch Gen Psychiatry 1993;50:205-211.
ABSTRACT  

A Linkage Study of Chromosome 11q in Schizophrenia
Wang et al.
Arch Gen Psychiatry 1993;50:212-216.
ABSTRACT  

Exclusion of Linkage Between the Serotonin2 Receptor and Schizophrenia in a Large Swedish Kindred
Hallmayer et al.
Arch Gen Psychiatry 1992;49:216-219.
ABSTRACT  

NO Association Between an Allele at the D2 Dopamine Receptor Gene (DRD2) and Alcoholism
Gelernter et al.
JAMA 1991;266:1801-1807.
ABSTRACT