Diagnostic Evaluation of Schizophrenia for Genetic Studies

Schizophrenia is one of the most severe mental disorders. Heredity is accepted as a major causative factor. To find molecular mechanisms behind schizophrenia, patient materials with reliable and valid diagnoses must be identified. In order to compare schizophrenia diagnostic procedures for reliability, validity and suitability for genetic studies by evaluation of record information, interview and register diagnostic data and to examine patient materials for linkage or association with molecular genetic markers three patient materials were recruited: sporadic cases, a large pedigree and sib-pairs. Schizophrenia diagnoses based on patient records only, showed good to excellent agreement with diagnoses based on both records and interviews. Register diagnoses generally displayed poor agreement with research diagnoses, but in 94% of patients sometimes registered as schizophrenic psychoses a research diagnosis of these disorders was certified. In the pedigree, analysis suggested linkage to chr 6p23 in a single branch of the pedigree, and a genome scan indicated linkage to the 6q25 region. A genome scan analysis of the sib-pair material was suggestive of linkage to chr 10q25.3-q26.3. In the case-control sample and a meta-analysis there was an association between a dopamine D2 receptor polymorphism (Ser311Cys), on chr 11q22-23, and the disorder. Brain-derived neurotrophic factor gene variants (chr 11p13) were also analysed without any robust significant findings. For patients in long-term treatment for schizophrenia in Sweden, psychiatric record reviews should be valid, reliable and sufficient for assessment of lifetime research diagnosis. Swedish register diagnosis of schizophrenic psychoses has a high positive predictive power in relation to corresponding research diagnoses. For future Swedish studies focusing on a broad definition of schizophrenia, it is sufficient to rely on the register diagnoses of schizophrenic psychosis. There is no major vulnerability gene or locus that is common to the majority of patients with schizophrenia, indicating genetic heterogeneity

A Schizophrenia-Susceptibility Locus at 6q25, in One of the World's Largest Reported Pedigrees

We have completed a genome scan of a 12-generation, 3,400-member pedigree with schizophrenia. Samples from 210 individuals were collected from the pedigree. We performed an “affecteds-only” genome-scan analysis using 43 members of the pedigree. The affected individuals included 29 patients with schizophrenia, 10 with schizoaffective disorders, and 4 with psychosis not otherwise specified. Two sets of white-European allele frequencies were used—one from a Swedish control population (46 unrelated individuals) and one from the pedigree (210 individuals). All analyses pointed to the same region: D6S264, located at 6q25.2, showed a maximum LOD score of 3.45 when allele frequencies in the Swedish control population were used, compared with a maximum LOD score of 2.59 when the pedigree's allele frequencies were used. We analyzed additional markers in the 6q25 region and found a maximum LOD score of 6.6 with marker D6S253, as well as a 6-cM haplotype (markers D6S253–D6S264) that segregated, after 12 generations, with the majority of the affected individuals. Multipoint analysis was performed with the markers in the 6q25 region, and a maximum LOD score of 7.7 was obtained. To evaluate the significance of the genome scan, we simulated the complete analysis under the assumption of no linkage. The results showed that a LOD score >2.2 should be considered as suggestive of linkage, whereas a LOD score >3.7 should be considered as significant. These results suggest that a common ancestral region was inherited by the affected individuals in this large pedigree