No Linkage Between D2 Dopamine Receptor Gene Region and Schizophrenia

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 D₂dopamine receptor densities in untreated schizophrenic patients support the D₂dopamine receptor gene as a strong candidate gene for schizophrenia. The recent cloning of the D₂dopamine receptor gene made it possible to test the involvement of the D₂dopamine 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 theDRD2locus and assuming a dominant mode of inheritance, we were able to exclude the_DRD2locus 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 D₂dopamine 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 theDRD2locus or the porphobilinogen deaminase locus. Our results do not support the D₂dopamine receptor hypothesis of schizophrenia. However, they cannot exclude the possibility that other genes regulating aspects of D₂dopamine expression might be involved in the etiology of schizophrenia, such as the expression of two D₂dopamine receptor subtypes by alternative RNA splicing.