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Serotonin Receptor 2C (HTR2C) and Schizophrenia: Examination of Possible Medication and Genetic Influences on Expression Levels
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
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2005 (English)In: American Journal of Medical Genetics, ISSN 0148-7299, Vol. 134B, 84-89 p.Article in journal (Refereed) Published
Abstract [en]

The serotonin receptor 2C (HTR2C) gene is of interest in schizophrenia due to its involvement in regulation of dopamine activity in the prefrontal cortex. We have previously reported a decreased expression of HTR2C mRNA levels in the prefrontal cortex of schizophrenia patients. The variability in mRNA expression levels is evaluated here more closely in relation to promoter haplotypes and neuroleptic treatment received by the patients. The decrease in HTR2C mRNA was present in neuroleptic treated individuals and in patients untreated at death, indicating that the lower expression is not a short-term medication effect. Three promoter polymorphisms were used to construct haplotypes. No SNP displayed genotypic or haplotypic association with the disease. Gene expression of HTR2C was not affected by haplotype and the expression decrease in schizophrenia patients was similar in all haplotype combinations (diplotypes). We conclude that the decrease in HTR2C expression in schizophrenia may be related to the disease mechanism rather than to drug treatment. The disease related changes in HTR2C expression are not related to the promoter variants typed in our sample, but could be due to other regulatory variants or trans-acting factors.

Place, publisher, year, edition, pages
2005. Vol. 134B, 84-89 p.
Keyword [en]
mRNA expression, neuroleptic drugs, psychiatric disease, serotonin receptor 2C, promoter polymorphisms
National Category
URN: urn:nbn:se:uu:diva-93323DOI: 10.1002/ajmg.b.30151PubMedID: 15717293OAI: oai:DiVA.org:uu-93323DiVA: diva2:166768
Available from: 2005-09-01 Created: 2005-09-01 Last updated: 2010-02-11Bibliographically approved
In thesis
1. Finding Genes for Schizophrenia
Open this publication in new window or tab >>Finding Genes for Schizophrenia
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Schizophrenia is one of our most common psychiatric diseases. It severely affects all aspects of psychological functions and results in loss of contact with reality. No cure exists and the treatments available today produce only partial relief for disease symptoms. The aim of this work is to better understand the etiology of schizophrenia by identification of candidate genes and gene pathways involved in the development of the disease.

In a preliminarily study, the effects of medication and genetic factors were investigated in a candidate gene, serotonin 2C receptor. This study distinguished pharmacological effects, caused by neuroleptics, and/or genetic effects, caused by unique polymorphisms, from other effects responsible for mRNA expression changes on candidate genes.

The core of the thesis describes a new candidate gene for schizophrenia, the quaking homolog, KH domain RNA binding (mouse) or QKI, located on chromosome 6q26-q27. The identification of QKI is supported by previous linkage studies, current association studies and mRNA expression studies using three different sample sets. The investigated samples included a 12-generation pedigree with 16 distantly related schizophrenic cases and their parents, 176 unrelated nuclear families with at least one affected child in each family and human brain autopsies from 55 schizophrenic cases and from 55 controls. Indirect evidence showing involvement of QKI in myelin regulation of central nervous system is presented. Myelin plays an important role in development of normal brains and disruption of QKI might lead to schizophrenia symptoms.

In a forth sample set, including extended pedigrees originated from a geographically isolated area above the Arctic Circle, in northeast Sweden, two additional schizophrenia susceptibility loci were identified, 2q13 and 5q21. Both these regions have previously been highlighted as potential schizophrenia loci in several other investigations, including a large Finnish study. This suggests common schizophrenia susceptibility loci for Nordic populations.

A pilot investigation including a genome wide haplotype analysis is presented. This statistical strategy could be further developed and applied to the artic Swedish families, including analysis of 900 microsatellites and 10,000 SNPs.

These findings will facilitate the understanding of the schizophrenia etiology and may lead to development of more efficient treatments for patients that suffer from schizophrenia.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 50 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 78
psychiatric genetics, QKI, large pedigree, haplotype investigation, mRNAexpression, genetic linkage, myelin, HTR2C
National Category
Biological Sciences
urn:nbn:se:uu:diva-5894 (URN)91-554-6308-8 (ISBN)
Public defence
2005-09-22, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:15 (English)
Available from: 2005-09-01 Created: 2005-09-01 Last updated: 2009-03-31Bibliographically approved

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