MOLECULAR GENETICS OF THE lq23.3 SCHIZOPHRENIA SUSCEPTIBILITY LOCUS

Family based linkage studies have confirmed that part of chromosome lq23.3 contains a susceptibility gene for schizophrenia. This region was investigated by tests of allelic and haplotypic association in order to fine map a specific gene in the lq23.3 region. Previously published studies claimed that the genes RGS4 and CAPON on lq23.3 were associated with schizophrenia. For this research thesis multiple markers were genotyped at the RGS4 and CAPON loci in a London based case control sample, no evidence for association was found. Therefore further fine mapping was carried out in the region between the RGS4 and CAPON genes. Allelic and haplotypic associations with schizophrenia were found with three microsatellite and four SNP markers within the serine threonine kinase (UHMK1) gene. A replication study using an Aberdeen based case control sample also found statistically significant evidence of allelic and haplotypic association between UHMK1 and schizophrenia. Re-sequencing of the UHMK1 gene was carried out in those individuals who had inherited alleles and haplotypes associated with schizophrenia. Three genetic variants were found. Genotyping of the whole case control sample showed that these changes were not associated with schizophrenia. The previously reported associations between schizophrenia and RGS4 as well as CAPON could possibly be explained by linkage disequilibrium between UHMK1 and both CAPON and RGS4. Alternatively there could be two or even three susceptibility genes within the 700 Kb region. At present no potential aetiological base pair changes have been detected in any of the three genes. UHMK1 is known to be highly expressed in regions of the brain implicated in schizophrenia and was found to be significantly down regulated in mice treated with the antipsychotic drug Clozapine. Further confirmation of the involvement of this gene in schizophrenia is needed followed by further efforts to detect genetic variation in or next to the gene which has an effect on expression and function of UHMK1.