LINKAGE, ASSOCIATION AND MUTATIONAL ANALYSIS OF THE DOPAMINE D3 RECEPTOR GENE IN SCHIZOPHRENIA

This study follows the observation of an association between homozygos ity of an MscI polymorphism in exon 1 and schizophrenia, which gives r ise to a glycine to serine substitution and may alter the functional p roperties of the receptor. Alternatively the polymorphism may not itse lf be of functional significance but may be in linkage disequilibrium with another genetic variant in the coding or regulatory regions. To e xamine the second possibility we have screened all six exons of DRD3 b y single-stranded conformational polymorphism analysis (SSCP) in 36 ca ses and 36 controls. Our findings suggest that the gene is highly cons erved since we found no other mutations which alter protein structure. However we did detect a 5-bp deletion in the 3' intronic sequence fla nking exon 5 which occurred in 7-8% of subjects within both case and c ontrol samples. A single bp substitution (g to a) in exon 3, which doe s not alter an amino acid was found in one affected individual. In add ition we carried out a linkage study of 24 families multiply affected with schizophrenia and a non-parametric linkage study of 90 affected s ibling pairs. These studies give no support for either major or modera te gene effects on schizophrenia susceptibility. Finally we have exten ded our association sample and observe a non-significant excess of hom ozygotes for the MscI polymorphism in the sample overall (chi(2)=2.09, 1 d.f., P=0.15). The excess of homozygotes is specific to males (chi( 2)=4.617, 1 d.f., P=0.032) and not females (chi(2)=0.243, 1 d.f., NS). When these data are added to our previous published data a highly sig nificant excess of homozygotes is observed in males (chi(2)=13.766, 1 d.f., P=0.00021) but not females (chi(2)=0.606, 1 d.f., NS). In conclu sion the accumulated data suggest strongly that genetic variation at t he DRD3 locus increases susceptibility of schizophrenia, at least in m ales. At present the MscI polymorphism in exon 1 of the gene remains a candidate for bringing about functional change in the receptor but th is has not been formally tested. Other coding region polymorphisms hav e not been detected but it remains possible that variation within the promoter may alter receptor function.