Diagnostic Evaluation of Schizophrenia for Genetic Studies

All previously published papers were reproduced with permission from the publishers. To Mattias and Frida The mind is its own place, and in itself Can make a Heav'n of Hell, a Hell of Heav'n-John Milton, Paradise Lost 2 3 ABSTRACT Background: Schizophrenia is one of the top-ten leading disorders causing disability worldwide. Heredity is accepted as a major causative factor but the mechanisms are still unknown. Molecular genetic studies have resulted in contradictory results. To find molecular mechanisms behind schizophrenia, patient materials with reliable valid diagnoses must be identified. The aims of the present thesis were: 1) to recruit Swedish patient materials with a conceivable diagnoses of schizophrenia and to certify these diagnoses. 2) to compare schizophrenia diagnostic procedures for reliability, validity and suitability for genetic studies by evaluation of record information, interview data and national register diagnostic data. 3) to examine the patient materials for linkage or association with molecular genetic markers. Three patient materials with schizophrenia were recruited, sporadic cases, a large pedigree with schizophrenia and Swedish sib-pairs. Results: Schizophrenia research diagnoses based only on patient records 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 (i.e. schizophrenia, schizoaffective psychosis or schizophreniform disorder) a research diagnoses of these disorders were certified. In the pedigree, analysis focussing on the short arm of chr 6 suggested linkage to 6p23 in a single branch of the pedigree, indicating heterogeneity within the family. In the same pedigree a whole genome scan indicated linkage to the 6q25 region. A whole genome scan analysis of the Swedish sib-pair material was suggestive of linkage to chr 10q25.3-q26.3. In the case-control sample there was an association between a putative functional dopamine D2 receptor polymorphism (Ser311Cys), on chr 11q22-23, and the disorder. This finding was apparent also in a meta-analysis of published studies. In the same patient material several brain-derived neurotrophic factor gene variants (chr 11p13) were also analysed without any robust significant findings. Conclusions: 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 of schizophrenia. A structured interview adds little new information. Swedish register diagnoses of schizophrenic psychoses have a high positive predictive power in relation to research diagnoses of these disorders. For future Swedish large-scale genetic studies …