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 receptors, the dopamine transporter, and G-proteins) in 59 families from Germany and Israel, for association. A P value of .00055 (.0044 when corrected for the no. of markers tested) was obtained for the intronic 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 spaced 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 affected pheotype was defined narrowly or broadly-as did nonparametric linkage (NPL). In 12 families with exclusively maternal transmission of the disease, the NPL value also supported linkage to this marker. In order to test for association/linkage disequilibrium in the presence of linkage, the sample was restricted to independent offspring. When this sample was combined with 65 additional simplex families (each of them comprising one schizophrenic offspring and his or her parents), the 124-bp allele of G-olf(alpha) was transmitted 47 times and was not transmitted 21 times (P = .009). These results suggest the existence, on chromosome 18p, of a potential susceptibility locus for functional psychoses.