Association of ZNF74 gene genotypes with age-at-onset of schizophrenia

Because of the manifestation of schizophrenic symptoms in individuals with interstitial deletions of chromosome 22q11.2, genes located in 22q11.2 are positional candidates for schizophrenia susceptibility. We genotyped five polymorphisms at D22S941, D22S944, D22S264, and D22S311, and the COMT gene in the common 3Mbp deletion region associated with 22q11 deletion syndrome in 300 Japanese schizophrenics and 300 controls and identified one patient with 22q11 deletion (Arinami et al., 2001). The results showed a trend of different genotypic distributions in D22S264 between patients with schizophrenia and controls (non-corrected p=0.04). Given this finding, we searched for mutations in the ZNF74 gene, which is located 11.2Kbp centromeric to D22S264. The ZNF74 gene is a member of the KRAB-zinc finger gene family and is expressed in the developing brain. Four polymorphisms, 1150T/C, IVS2a-40G/A, E/K46, and [K/N551;L/F552], were detected. The first three polymorphisms were in almost complete linkage disequilibrium. Case-control comparisons for these polymorphisms resulted in similar genotypic and allelic frequencies in patients and controls. The polymorphisms, however, were significantly associated with age-at-onset of schizophrenia (n<0.0001). Subsequent analyses in another Japanese schizophrenic population (n=169) confirmed an age-at-onset association (p<0.0001). These findings suggest that the ZNF74 gene plays a role as one of the modifying factors for schizophrenia.