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We have previously shown that chromosome 6q25-6q27 includes a susceptibility locus for schizophrenia in a large pedigree from northern Sweden. In this study, we fine-mapped a 10.7 Mb region, included in this locus, using 42 microsatellites or SNP markers. We found a 0.5 Mb haplotype, likely to be inherited identical by decent, within the large family that is shared among the majority of the patients (69%). A gamete competition test of this haplotype in 176 unrelated nuclear families from the same geographical area as the large family showed association to schizophrenia (empirical P-value 0.041). The only gene located in the region, the quaking homolog, KH domain RNA binding (mouse) (QKI), was investigated in human brain autopsies from 55 cases and 55 controls using a high-resolution mRNA expression analysis. Relative mRNA expression levels of two QKI splice variants were clearly downregulated in schizophrenic patients (P-value 0.0004 and 0.03, respectively). The function of QKI has not been studied in humans, but the mouse homolog is involved in neural development and myelination. In conclusion, we present evidence from three unrelated sample-sets that propose the involvement of the QKI gene in schizophrenia. The two family based studies suggest that there may be functional variants of the QKI gene that increase the susceptibility of schizophrenia in northern Sweden, whereas the case-control study suggest that splicing of the gene may be disturbed in schizophrenic patients from other geographical origins. Taken together, we propose QKI as a possible target for functional studies related to the role of myelination in schizophrenia.

We have previously shown that chromosome 6q25-6q27 includes a susceptibility locus for schizophrenia in a large pedigree from northern Sweden. In this study, we fine-mapped a 10.7 Mb region, included in this locus, using 42 microsatellites or SNP markers. We found a 0.5 Mb haplotype, likely to be inherited identical by decent, within the large family that is shared among the majority of the patients (69%). A gamete competition test of this haplotype in 176 unrelated nuclear families from the same geographical area as the large family showed association to schizophrenia (empirical P-value 0.041). The only gene located in the region, the quaking homolog, KH domain RNA binding (mouse) (QKI), was investigated in human brain autopsies from 55 cases and 55 controls using a high-resolution mRNA expression analysis. Relative mRNA expression levels of two QKI splice variants were clearly downregulated in schizophrenic patients (P-value 0.0004 and 0.03, respectively). The function of QKI has not been studied in humans, but the mouse homolog is involved in neural development and myelination. In conclusion, we present evidence from three unrelated sample-sets that propose the involvement of the QKI gene in schizophrenia. The two family based studies suggest that there may be functional variants of the QKI gene that increase the susceptibility of schizophrenia in northern Sweden, whereas the case-control study suggest that splicing of the gene may be disturbed in schizophrenic patients from other geographical origins. Taken together, we propose QKI as a possible target for functional studies related to the role of myelination in schizophrenia.

We aimed to estimate the value of structured interviews, medical records and Swedish register diagnoses for assessing lifetime diagnosis of patients with schizophrenia. Psychiatric records and diagnostic interviews of 143 Swedish patients diagnosed by their treating physician with schizophrenia and related disorders were scrutinized. Based on record analysis only, or a combined record and interview analysis, DSM-IV diagnoses were obtained by the OPCRIT algorithm. Independent of the OPCRIT algorithm, a standard research DSM-IV diagnosis, based on both record and interview analysis, was given by the research psychiatrist. Concordance rates for the different psychosis diagnoses were calculated. DSM-IV diagnoses based on records only, showed a good to excellent agreement with diagnoses based on records and interviews. Swedish register diagnoses displayed generally poor agreement with the research diagnoses. Nevertheless, 94% of subjects sometimes registered with a diagnosis of schizophrenic psychoses (i.e. schizophrenia, schizoaffective psychosis or schizophreniform disorder) displayed a standard research DSM-IV diagnosis of these disorders. For patients in long-term treatment for schizophrenia in Sweden, psychiatric record reviews should be optimal, cost effective and sufficient for assessment of lifetime research diagnoses of schizophrenia. For these patients a research interview adds little new information. The results further indicate that a Swedish register diagnosis of schizophrenic psychoses has a high positive predictive power to a standard research DSM-IV diagnosis of the disorders. It is concluded that for future Swedish large-scale genetic studies focusing on a broad definition of schizophrenia, it would be sufficient to rely on the Swedish register diagnoses of schizophrenic psychosis.

We searched for candidate chromosomal regions inherited identical by descent in 19 patients suffering from schizophrenia or schizoaffective disorder that are related 12 generations back, to an ancestral couple born in the middle of the seventeenth century. To accomplish this goal, we constructed complete chromosomal haplotypes for each patient using genotype data from 450 markers. In total, 12 haplotype regions (with sizes ranging from 0.6 to 10.9 cM) constituted by three markers each were identical in three or more of the affected individuals. The largest genomic segment was located on 6q25, a region previously shown to be significantly more frequent in patients than controls, and proposed to contain a schizophrenia susceptibility locus. For the remaining 11 candidate haplotypes, we estimated haplotype frequencies from all the 43 affected members collected from the same family and 46 unrelated control individuals. This analysis indicated that at least four of the 11 candidate haplotypes are ancestral, since the frequencies were significantly higher in patients than in controls. Five additional haplotypes showed higher estimated frequencies in the patients but the differences were not significant. Interestingly, five of these 11 genomic regions are located in, or close to, candidate regions previously suggested to contain susceptibility genes for schizophrenia. The regions are 5q21-23, 8p21-22, 10p13-15, 13q12-13 and 22q12-13. Several of these haplotypes are probably ancestral linkage disequilibrium blocks inherited from the original couple. There exists, however, the possibility that one or more of these regions harbour schizophrenia susceptibility loci that may have epistatic interactions among them.

Nineteen parent-offspring pairs obtained from 14 two-generation families with available medical records and diagnosis of schizophrenia were studied to compare the ages of onset of the parent generation with those of the offspring generation. The mean age of onset for the parent generation was 37.3 +/- 6.0 years and for the offspring generation was 20.8 +/- 4.4. The mean difference was thus 16.5 +/- 6.2, suggesting the occurrence of anticipation in schizophrenia (p < 0.001). Although some ascertainment biases (like reduced fertility in early-onset parents or early detection of symptoms in offsprings of affected parents) may partially contribute to the occurrence of anticipation, this study replicates recent reports of anticipation in several neuropsychiatric disorders, some of which have been shown to be associated with unstable expansions of trinucleotide repeats in the genomic DNA.