SUPPORT FOR A CHROMOSOME 18P LOCUS CONFERRING SUSCEPTIBILITY TO FUNCTIONAL PSYCHOSES IN FAMILIES WITH SCHIZOPHRENIA, BY ASSOCIATION AND LINKAGE ANALYSIS

The action of antipsychotic drugs on dopamine receptors suggests that dopaminergic signal transmission may play a role in the development of schizophrenia. We tested eight candidate genes (coding for dopamine r eceptors, the dopamine transporter, and G-proteins) in 59 families fro m Germany and Israel, for association. A P value of .00055 (.0044 when corrected for the no. of markers tested) was obtained for the introni c CA-repeat marker G-olf(alpha) on chromosome 18p. The value decreased to .000088 (.0007) when nine sibs with recurrent unipolar depressive disorder were included. Linkage analysis using SSLP markers densely sp aced around G-olf(alpha) yielded a maximum two-point LOD score of 3.1 for a marker 0.5 cM distal to G-olf(alpha). Multipoint analysis under the assumption of heterogeneity supported this linkage-whether the aff ected pheotype was defined narrowly or broadly-as did nonparametric li nkage (NPL). In 12 families with exclusively maternal transmission of the disease, the NPL value also supported linkage to this marker. In o rder to test for association/linkage disequilibrium in the presence of linkage, the sample was restricted to independent offspring. When thi s sample was combined with 65 additional simplex families (each of the m comprising one schizophrenic offspring and his or her parents), the 124-bp allele of G-olf(alpha) was transmitted 47 times and was not tra nsmitted 21 times (P = .009). These results suggest the existence, on chromosome 18p, of a potential susceptibility locus for functional psy choses.