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Diagnostic Evaluation of Schizophrenia for Genetic Studies
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Umeå: Klinisk vetenskap , 2005. , 70 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 993
Keyword [en]
Psychiatry, Schizophrenia, Diagnostic evaluation, Molecular genetic studies, Linkage, Association
Keyword [sv]
Psykiatri
National Category
Psychiatry
Research subject
Psychiatry
Identifiers
URN: urn:nbn:se:umu:diva-637ISBN: 91-7305-970-6 (print)OAI: oai:DiVA.org:umu-637DiVA: diva2:144084
Public defence
2005-12-09, D, Tandläkarhögskolan, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2005-11-17 Created: 2005-11-17 Last updated: 2010-05-06Bibliographically approved
List of papers
1. Evaluation of diagnostic procedures in Swedish patients with schizophrenia and related psychoses.
Open this publication in new window or tab >>Evaluation of diagnostic procedures in Swedish patients with schizophrenia and related psychoses.
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2005 (English)In: Nordic Journal of Psychiatry, ISSN 0803-9488, E-ISSN 1502-4725, Vol. 59, no 6, 457-464 p.Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-27108 (URN)10.1080/08039480500360906 (DOI)16316898 (PubMedID)
Available from: 2009-11-11 Created: 2009-11-11 Last updated: 2017-12-12
2. Linkage analysis of a Swedish kindred provides further support for a susceptibility locus for schizophrenia on chromosome 6p23
Open this publication in new window or tab >>Linkage analysis of a Swedish kindred provides further support for a susceptibility locus for schizophrenia on chromosome 6p23
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1999 (English)In: American Journal of Medical Genetics, ISSN 0148-7299, E-ISSN 1096-8628, Vol. 88, no 4, 369-377 p.Article in journal (Refereed) Published
Abstract [en]

Several reports have indicated genetic linkage between markers on the short arm of chromosome 6 and schizophrenia. However, significant threshold levels were not always achieved, and the chromosomal regions identified are large and different in different families. One way to decrease the problem of heterogeneity is to study a single extended pedigree. Here we report the analysis of a very large, previously undescribed pedigree from northern Sweden that includes 31 affected individuals. We typed 16 markers spanning 40 cM on the short arm of chromosome 6. Linkage analysis was performed only with the affected individuals. Suggestive lod scores (maximum 2.6) were obtained with markers on chromosome 6p23 in a single branch of the large pedigree indicating possible heterogeneity inside the family. A haplotype comprising markers from D6S309 to D6S1578 was found to segregate with the disease. This chromosomal region is included within a segment proposed to contain a susceptibility gene for schizophrenia by many other investigators. Our results thus give further support for a possible localization of a susceptibility locus for schizophrenia in 6p23 and help to narrow the candidate chromosomal region to the segment included between markers D6S309 and D6S1578. Copyright 1999 Wiley-Liss, Inc.

Keyword
schizophrenia, chromosome 6, disease susceptibility, lod score
Identifiers
urn:nbn:se:umu:diva-4829 (URN)10.1002/(SICI)1096-8628(19990820)88:4<369::AID-AJMG14>3.0.CO;2-9 (DOI)10402504 (PubMedID)
Available from: 2005-11-17 Created: 2005-11-17 Last updated: 2017-12-14Bibliographically approved
3. A schizophrenia-susceptibility locus at 6q25, in one of the world´s largest reported pedigree
Open this publication in new window or tab >>A schizophrenia-susceptibility locus at 6q25, in one of the world´s largest reported pedigree
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2001 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 69, no 1, 96-105 p.Article in journal (Refereed) Published
Abstract [en]

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.

Identifiers
urn:nbn:se:umu:diva-4830 (URN)10.1086/321288 (DOI)11389481 (PubMedID)
Available from: 2005-11-17 Created: 2005-11-17 Last updated: 2017-12-14Bibliographically approved
4. A systematic genomewide linkage study in 353 sib pairs with schizophrenia.
Open this publication in new window or tab >>A systematic genomewide linkage study in 353 sib pairs with schizophrenia.
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2003 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 73, no 6, 1355-1367 p.Article in journal (Refereed) Published
Abstract [en]

We undertook a genomewide linkage study in a total of 353 affected sib pairs (ASPs) with schizophrenia. Our sample consisted of 179 ASPs from the United Kingdom, 134 from Sweden, and 40 from the United States. We typed 372 microsatellite markers at approximately 10-cM intervals. Our strongest finding was a LOD score of 3.87 on chromosome 10q25.3-q26.3, with positive results being contributed by all three samples and a LOD-1 interval of 15 cM. This finding achieved genomewide significance (P<.05), on the basis of simulation studies. We also found two regions, 17p11.2-q25.1 (maximum LOD score [MLS] = 3.35) and 22q11 (MLS = 2.29), in which the evidence for linkage was highly suggestive. Linkage to all of these regions has been supported by other studies. Moreover, we found strong evidence for linkage (genomewide P<.02) to 17p11.2-q25.1 in a single pedigree with schizophrenia. In our view, the evidence is now sufficiently compelling to undertake detailed mapping studies of these three regions.

Identifiers
urn:nbn:se:umu:diva-27109 (URN)10.1086/380206 (DOI)14628288 (PubMedID)
Available from: 2009-11-11 Created: 2009-11-11 Last updated: 2017-12-12
5. Dopamine D2 receptor gene Ser311Cys variant and schizophrenia: Association study and meta-analysis
Open this publication in new window or tab >>Dopamine D2 receptor gene Ser311Cys variant and schizophrenia: Association study and meta-analysis
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2003 (English)In: American Journal of Medical Genetics, ISSN 0148-7299, E-ISSN 1096-8628, Vol. 119B, no 1, 28-34 p.Article in journal (Refereed) Published
Abstract [en]

An association has been reported between a dopamine D(2) receptor gene (DRD2) Ser311Cys variant and schizophrenia. In a replication attempt, Swedish patients with schizophrenia (n = 173) and control subjects (n = 236) were assessed for the DRD2 Ser311Cys variant. Schizophrenic patients displayed higher Cys311 allele frequencies than control subjects (4.0 vs. 0.8%, chi(2) = 9.49, df = 1, P = 0.002; odds ratio (OR) 4.93, 95% confidence interval (95% CI) 1.61-15.12). The association was detected only in men. The results were supported by a meta-analysis of all published case-control studies comprising a total of 9,152 subjects (chi(2) = 11.37, df = 1, P < 0.001; OR 1.43, 95% CI 1.16-1.78). The present results support the involvement of the DRD2 gene in the pathogenesis of schizophrenia. Copyright 2003 Wiley-Liss, Inc.

Keyword
genetics, dopamine D2 receptor gene locus (DRD2), dopamine receptors
Identifiers
urn:nbn:se:umu:diva-4832 (URN)10.1002/ajmg.b.20004 (DOI)12707934 (PubMedID)
Available from: 2005-11-17 Created: 2005-11-17 Last updated: 2017-12-14Bibliographically approved
6. Brain-derived neurotrophic factor gene (BDNF) variants and schizophrenia: an association study
Open this publication in new window or tab >>Brain-derived neurotrophic factor gene (BDNF) variants and schizophrenia: an association study
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Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-4833 (URN)
Available from: 2005-11-17 Created: 2005-11-17 Last updated: 2010-01-13Bibliographically approved

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