Genetic studies of schizophrenia

University dissertation from Uppsala : Acta Universitatis Upsaliensis

Abstract: The prevalence of schizophrenia is about 1% throughout the world. The disease is characterized by symptoms such as hallucinations, delusions and bizarre behavior. A genetic contribution to the disease was previously shown through epidemiological studies. The mitochondrial DNA was sequenced in four schizophrenic patients. This investigation followed a previous study where a 50% reduction in cytochrome c oxidase (COX) activity was found in brain tissue from schizophrenic patients. Five substitutions located in coding regions were discovered. Further investigations of the variants in 88 patients and 350 controls did not lend support for a mitochondrial mutation in the aetiology of schizophrenia. A large pedigree from Northern Sweden with members showing an increased frequency of schizophrenia was analyzed for the presence of susceptibility locus/loci for schizophrenia. The 6p2l-23 region was analyzed first, because it was previously suggested to contain a schizophrenia susceptibility locus. In one branch of the pedigree, a suggestive lod score value and a segregating haplotype was found on 6p23. However, this haplotype did not segregate in other branches, suggesting that other susceptibility loci may segregate with the disease. Therefore, we conducted a genome wide search to indentify additional candidate loci for schizophrenia in the large pedigree. The highest lod score obtained was on 6q25. Additional markers were typed within the region. One of the markers (D6S253) reached a two-point lod score of 6.6 and multipoint analysis gave a maximum lod score of 7.7. A haplotype was found that segregated with affected individuals. To investigate if other large genomic segments were inherited identical by descent (IBD) within the large pedigree, haplotypes were constructed in all chromosomes. This was done for 19 affected individuals. Twelve regions were IBD candidate segments, which were shared by at least three individuals. Five of the 12 regions are located near or within regions previously suggested to contain susceptibility genes for schizophrenia. There is a possibility that epistatic interaction may exist between genes located in some of these regions.

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