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Title: Use of high-throughput sequencing technologies to study the genetic basis of monogenic and complex diseases
Author: Thomas, Ellen Rachel Amy
ISNI:       0000 0004 2741 8757
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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The study of Mendelian and complex diseases has accelerated rapidly over the last decade, due to developments in knowledge and understanding of the human genome, and the application of high-throughput technologies to a wide range of questions. In this project, the common treatable Mendelian disease familial hypercholesterolaemia (FH) and the polygenic autoimmune disease systemic lupus erythematosus (SLE) were studied by targeted resequencing of small genomic regions and larger exome sequencing experiments. The targeted resequencing protocols were developed in the course of the project against a background of rapid technological advances in the commercial and academic sectors in this field. In FH, known and novel genes were studied in patient cohorts from two lipid clinics, and families with no identifiable mutation were followed up using linkage analysis and exome sequencing. Functional data were also generated to establish a novel variant in APOB as the likely cause of hypercholesterolaemia in one such family. The relationship between polymorphisms in SLCO1B1 and adverse reactions to statin drugs used to treat FH was also investigated, and the application of novel protocols in diagnostic testing and screening was also considered. In SLE, targeted resequencing was applied to the ITGAM gene which encodes a component of complement receptor 3 (CR3); ITGAM had previously been associated with the disease in multiple genome-wide association studies. Two rare variants were detected in a patient with SLE, and these have been found to have an effect on the phagocytic capability of CR3, which is likely to have contributed to these patients’ disease process. This project has compared the strengths and limitations of experiments employing high-throughput sequencing protocols in Mendelian and complex disease, and has contributed to protocol development as well as increasing understanding of the genetic basis of FH and SLE.
Supervisor: Aitman, Tim ; Vyse, Tim Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available