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Title: The genetics of inflammatory bowel disease in extended multiplex Ashkenazi Jewish kindreds
Author: Levine, A. P.
ISNI:       0000 0004 5364 8177
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2015
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The inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis, are chronic inflammatory diseases predominantly affecting the gastrointestinal tract. They are of unknown aetiology; however, there is a significant genetic component. A multitude of studies have identified common genetic variants associated with these diseases; however, they only account for a proportion of the disease heritability. The study of large families with many affected individuals is theoretically a powerful method for identifying rare disease causing variants that might contribute to this ‘missing heritability’. To date, this approach has not been successfully employed in IBD owing, in part, to the moderate size of families identified. This thesis describes the ascertainment, phenotypic and genomic characterisation of two extended multi-plex Ashkenazi Jewish (AJ) kindreds with over 50 and 25 cases of IBD, respectively. An interrogation of the possible mechanisms underlying this familial aggregation highlighted a partial role for common disease associated variants. Linkage analysis was employed in an attempt to identify loci segregating with the disease. A novel method for reconstructing haplotype flow information across extended pedigrees is described and implemented in these kindreds demonstrating the absence of a single locus shared by all affected individuals. Exome sequencing a cohort of unrelated AJ individuals and cases from the families permitted the prioritisation of a number of candidate variants however, these did not reach an empirical significance thresh-old as defined using a Monte Carlo gene-dropping approach. It is possible that the analyses of these data in combination with those from additional families may yield significance. However it is clear that even in extended families with many affected individuals, the genetics of IBD remains complex.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available