| Summary: | I have studied four families that show linkage of psychiatric illness to chromosome 4p. Linkage was first observed in a large family, F22 segregating bipolar and unipolar affective disorders. Subsequently, a smaller family, F59, segregating affective disorders and two families (F50 & F48) segregating schizophrenia, schizoaffective and bipolar disorders confirmed this linkage. Previously, comparison of the two haplotypes inherited with illness in each family allowed prioritisation of two sub-regions for detailed study. Minimal Region 1 (MR1) is defined by overlap of the disease chromosomes from three Celtic families (F22, F59 & F50). Minimal Region 2 (MR2) is defined by the two largest families F22 and F48, as well as F50. The sequence available from the human genome sequencing project for these two regions is largely complete. Here, I describe an extension to the BAC map in the repetitive telomeric end of MR1. The telomeric end of MR1 is defined by a recombination event in an individual from F50. I describe construction of a transcript map of MR1 and 2 using bioinformatics methods, RT-PCR and cDNA library screening. I then selected two candidate genes from this region: orphan g protein coupled receptor 78 (GPR78) and superoxide dismutase 3 (SOD3), for further study. Firstly, I identified SNPs in the genes from the linked families, and then carried out a preliminary association study on 100 Schizophrenic patients, 100 Bipolar Affective disorder patients 100 controls. The linkage disequilibrium (LD) between the markers was measured and, using a low stringency significant p-value cut off, revealed a positive association in GPR78. SNPs were then tested on a larger population for association. This work adds to the case for studying chromosome 4 for its role in the genetic susceptibility to affective disorder.
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