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Fabio Macciardi, MD, PhD; Arturas Petronis, MD, PhD; Hubert H. M. Van Tol, PhD; Cecilia Marino, MD; M. Cristina Cavallini, MD; Enrico Smeraldi, MD; James L. Kennedy, MD

Arch Gen Psychiatry. 1994;51(4):288-293.

Abstract
Background
Among the different dopamine receptors, the D₄ dopamine receptor is of particular interest in schizophrenia because of its high affinity for the atypical neuroleptic clozapine. Recently, the gene for the D₄ dopamine receptor has been cloned and a new and intriguing polymorphism has been described. Different versions of the receptor have varying affinity for clozapine, and thus variant forms of D₄ with differing pharmacologic activity exist in the human population. Our hypothesis was that these variants play a role in susceptibility to psychotic illness. Thus, our objective was to test the D₄ dopamine receptor genes for linkage to schizophrenia.

Methods
Our genetic linkage study was carried out in a large Italian kindred segregating schizophrenia. Diagnoses were made by using a structured clinical interview and a consensus diagnosis was established. For the computer analysis, 80 members of the family were constructed into a linked set of relatives with 15 of these individuals affected by schizophrenia. The functional variants of the D₄ dopamine receptor gene were identified by a combination of Southern blot techniques and the polymerase chain reation. The gene for tyrosine hydroxylase (TH) was also tested for linkage to schizophrenia in this family. Linkage analyses were done with both a single-locus and a two-locus model.

Results
Our results revealed significantly negative lod scores in the region of the D₄ dopamine receptor gene and the TH gene. The application of different models of transmission for schizophrenia had an effect on the magnitude of the lod scores, but did not modify the direction of the results.

Conclusions
Our results provide significant evidence for exclusion for linkage between schizophrenia and the dopamine D₄ receptor gene and the TH gene under the models specified. Furthermore, we tabulated the distribution of D₄ dopamine gene variants in the diseased vs healthy individuals in the family and the results showed that no specific form of the receptor gene is significantly asociated with the presence of schizophrenia in the family. Our study does not exclude the possibility that regulatory elements of the D₄ dopamine gene located elsewhere in the genome may be involved in the etiology of schizophrenia.

Author Affiliations
From the Istituto Scientifico H San Raffaele, Department of Neuroscience, University of Milano (Italy) School of Medicine (Drs Macciardi, Marino, Cavallini, and Smeraldi); and the Sections of Neurogenetics (Drs Petronis and Kennedy) and Molecular Psychobiology (Dr Van Tol), the Clarke Institute of Psychiatry, University of Toronto, Ontario.

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