Linkage disequilibrium mapping and candidate gene screening of the VCFS deleted region for mutations associated with schizophrenia

Velo-cardio-facial syndrome (VCFS) is associated with small interstitial deletions of chromosome 22q11. Patients with VCFS have a high risk of developing schizophrenia. Kimber and colleagues have deleted a 150kb fragment from the region on murine chromosome 16 syntenic to the VCFS critical region. Interestingly, mice heterozygous for this deletion displayed an increase in prepulse inhibition (PPI) of the startle response which is considered by some to model aspects of the schizophrenia phenotype. This suggests that the genes that map within this 150kb fragment should be considered strong candidate genes for psychosis. We have now screened the human homologues of the 6 genes contained within the murine 150kb deletion (Znf741, DGCR2, Stk22a, DGSI, GscI, and Slc25A1) for sequence variants using DHPLC and sequencing. Non- synonymous SNP's have been genotyped in a stage one association sample of 174 DSM-IV schizophrenic patients and 174 matched controls together with a further 81 subjects that had been ranked according to their PPI measurement. In addition we have used both microsatellites and SNP's to perform LD mapping across the VCFS deleted region in an attempt to refine the location of a schizophrenia susceptibility locus.