OBJECTIVES: From the hypothesis that an impaired insulin and insulin-like growth factor cellular signalling in brain and body might result in the development of schizophrenia or related psychoses, I in this study chose to thoroughly investigate the insulin receptor gene in patients with schizophrenia or schizoaffective disorder and controls. METHODS: For identification of single nucleotide polymorphisms (SNPs) of interest in the insulin receptor gene, targeted whole gene sequencing of DNA using the SOLiD technology was first carried out in two subgroups of the study population: 1) 49 schizophrenia or schizoaffective disorder patients with heredity for schizophrenia or related psychoses, and 2) 25 controls. Ten possible SNPs of interest were identified and these were then typed by standard methods in the whole study population consisting of 105 patients with schizophrenia or schizoaffective disorder and 60 controls. RESULTS: In comparisons between schizophrenia patients, schizoaffective disorder patients and controls, overall significant differences were found in genotype distribution and allele frequency for SNP rs2229431 in exon 13, and tendencies towards overall significant differences were found for SNP rs12610022 in intron 13, but not for the other 8 possible SNPs investigated. It was the patients with schizoaffective disorder who differed in genotype distributions and allele frequencies compared to both the patients with schizophrenia and the controls, whereas between the patients with schizophrenia and the controls, no significant differences were found. CONCLUSION: The results of this study show that two gene variants in exon and intron 13 of the insulin receptor gene confer risk specifically for schizoaffective disorder.