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Molecular genetics of the chromosome 11q22-24 schizophrenia susceptibility region

Choudhury, Khalid Hussain; (2008) Molecular genetics of the chromosome 11q22-24 schizophrenia susceptibility region. Doctoral thesis , UCL (University College London). Green open access

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Linkage analyses of multiply affected schizophrenic families have confirmed the involvement of the chromosome 11q22-24 region in the aetiology of schizophrenia, with LOD scores of 3.4 and 3.1. As a result, a genetic association study was performed to fine map this area by detecting linkage disequilibrium between DNA markers and the genetic disorder. This was done using the University College London (UCL) sample of 496 cases and 488 supernormal controls. Seven microsatellite or SNP markers localised within or near the FXYD6 gene showed empirically significant allelic associations with schizophrenia. Confirmation was then performed by the study of an Aberdeen sample consisting of 858 cases and 591 controls. Here, two of the SNPs replicated association with schizophrenia. Sequencing of the FXYD6 gene led to the discovery of several mutations including a rare non-database SNP, which was found at a significantly higher frequency in the selected high risk haplotype schizophrenic patients, when compared to the randomly chosen control individuals. However, a genetic association test of this SNP was found to be negatively associated to schizophrenia when genotyping in the whole UCL case-control sample. FXYD6 encodes for the protein phosphohippolin and functions by modulating the kinetic properties of Na,K-ATPase to the specific requirements of a given tissue, cell type or physiological state. Phosphohippolin is predominantly expressed in the brain, with strong expression in the hippocampus and the cerebellum. The prominent levels of FXYD6 expression in regions of the brain thought to be involved in schizophrenia provide strong support that the FXYD6 gene increases genetic susceptibility to schizophrenia. Further confirmations involving FXYD6 to schizophrenia are essential in other case-control samples. In addition, aetiological base pair changes in FXYD6 or in associated promoter/control regions that cause an abnormal function or expression of phosphohippolin require detection.

Type: Thesis (Doctoral)
Title: Molecular genetics of the chromosome 11q22-24 schizophrenia susceptibility region
Identifier: PQ ETD:591475
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest. Third party copyright material has been removed from the ethesis. Images identifying individuals have been redacted or partially redacted to protect their identity.
UCL classification:
URI: https://discovery.ucl.ac.uk/id/eprint/1444173
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