Blaveri, Ekaterini; (2000) Molecular genetics of the 8p21-22 schizophrenia susceptibility locus. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Evidence for a susceptibility locus for schizophrenia mapping to chromosome 8p21-p22 has been reported by several investigators. This thesis will describe work carried out in order to narrow down the susceptibility area on this chromosomal region making it amenable to positional cloning and positional candidate studies. A linkage study was performed in 16 English families containing cases of schizophrenia with five microsatellite polymorphisms on chromosome 8p21-p22. No evidence of linkage was obtained between any of these markers and schizophrenia in this family sample. Next, case-control allelic association studies were performed in order to assess the candidacy of prepronociceptin (PNOC) and neuronal nicotinic acetylcholine receptor subunit alpha 2 (CHRNA2) genes, in this region. No evidence of allelic association was found between the DNA variations at or near the two genes that were examined and schizophrenia in the London (UK) case-control sample. Linkage disequilibrium mapping was also performed in order to narrow down the region of chromosome 8p21-22 that is implicated in schizophrenia. An allelic association was obtained between microsatellite marker D8S261 and schizophrenia (CLUMP T3: χ2=9,9929, p=0.01) in the London (UK) case-control sample. Analysis of additional polymorphisms covering a region of ~700 kb around this marker in our population sample also revealed significant evidence for allelic association between schizophrenia and two novel, neighbouring polymorphisms, D8S2616 (CLUMP T1: χ2=19.9236,p=0.024) and D8S2615 (CLUMP T1: χ2=15.1777, p=0.004). The three markers, D8S261, D8S2616 and D8S2615 cover a region of approximately 108 kb on the 8p21.3-22 region and also showed statistically significant marker-to-marker linkage disequilibrium. A replication study was attempted in two case-control samples of Scottish ancestry. The first case-control Scottish sample consisting of 100 cases and 100 controls did not show evidence of allelic association between any of the three previously associated markers and schizophrenia. The second case-control Scottish sample consisting again of 100 cases and 100 controls demonstrated evidence of allelic association only between D8S2616 and schizophrenia (CLUMP T1: χ2= 16.3893, p=0.043). The two case-control Scottish samples were combined but failed to demonstrate allelic association with any of the three positive markers. Finally, significant allelic association was obtained by the CLUMP T3 statistic between D8S261 (χ2=7.9706, p=0.047), D8S2616 (χ2=8.1593, p=0.033), D8S2615 (χ2=5.9546, p=0.05) and schizophrenia when all three case-control samplesr where combined together. The microsatellite markers, D8S261 and D8S2616 are localised in the intronic region of the pericentriolar material 1 (PCM1) gene on chromosome 8p21.3-22 while D8S2615 lies 75 kb upstream the translation initiation codon of this gene. The study of the DNA variation of this gene is underway in order to assess its possible involvement in the liability to schizophrenia. Some preliminary data are described in this thesis.

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