A STUDY OF CHROMOSOME 4P MARKERS AND DOPAMINE D5 RECEPTOR GENE IN SCHIZOPHRENIA AND BIPOLAR DISORDER

There are several lines of evidence which suggest that chromosome 4p m ay contain a major susceptibility locus for the functional psychoses. We previously reported a family (family 50) with cases of schizophreni a and schizoaffective disorder which gave maximum lod scores of 1.96 a nd 1.84 respectively with the markers D4S403 and a microsatellite near to DRD5 (DRD5-M). More recently Blackwood and co-workers described a family segregating bipolar and unipolar affective disorders which give s a maximum lod score of 4.1 with the marker D4S394, which lies 10 cM from D4S403. They obtained a combined maximum lod of 3.3 in their tota l sample of 12 bipolar families and found significant evidence of hete rogeneity (chi(2) = 18.8, df = 2, P = 0.00008). Here we report the res ults of a linkage study of chromosome 4p markers in a sample of 24 mul tiply affected families with schizophrenia and related disorders. We o btained an overall maximum lod of 1.12 with D4S403 under both dominant and recessive modes of transmission, with no statistical support for heterogeneity within our sample. Examination of family by family data shows that only family 50 appears to show linkage at this locus. Howev er, a discrepancy exists since our study examined families fulfilling criteria for a linkage study of schizophrenia while Blackwood et al ex amined families included in a genetic linkage study of bipolar disorde r. This may be explained by the clinical features displayed by members of family 50, which show that all the affected members have some affe ctive symptoms. It is therefore possible that a broad phenotype includ ing unipolar depression, bipolar disorder, schizoaffective disorder an d schizophrenia when accompanied by significant affective symptoms can result from mutations within a gene in this region. The dopamine D5 r eceptor gene lies within the region identified by the linkage studies and is therefore a major candidate for the putative disease gene. In f amily 50 we have looked for mutations of DRD5 by sequence analysis of the coding region and single stranded conformational polymorphism (SSC P) analysis of the promoter. SSCP analysis of the coding and promoter regions have also been carried out in unrelated cases of DSM-IIIR schi zophrenia. Finally association studies of the (TC), repeat in the prom oter and schizophrenia, and DRD5-M and bipolar disorder were performed . These studies provided no further evidence supporting the possibilit y that mutations in DRD5 give rise to the linkage findings or are acti ng as susceptibility loci in schizophrenia or bipolar disorder.