| dc.description.abstract | The genome‐wide association study era has identified numerous loci associated with many
common polygenic diseases. The next challenge is to identify the functional consequences
of these variants and elicit how they impact on disease risk. Using a combination of protein
based assays, large scale microarrays and high‐throughput generation sequencing
platforms this thesis aims to identify the functional effects of disease loci, with particular
focus on Crohn’s disease and coeliac disease, two common complex gastrointestinal
diseases.
Variants located within the Interleukin 23 receptor are associated with both susceptibility
and protection from Crohn’s disease, a debilitating chronic inflammatory disease of the
bowel. A study was undertaken to investigate the effect of these variants, at the mRNA as
well as the protein level, on both cytokine and receptor levels.
Coeliac disease is a dietary intolerance to the gluten component of wheat, barley and rye
and has an estimated prevalence of approximately 1%. Genome‐wide association studies
have identified eight genomic different loci as associated with coeliac disease but none
have been functionally characterised. To investigate the effect that genotype has on gene
transcript levels, a genetical genomics study was undertaken in patients with coeliac
disease generating results with relevance to a range of autoimmune disorders.
Before disease based effects can be identified, it is first important to fully characterise the
normal human transcriptome and methylome. To this end CD4
+ T cells were studied using
novel high‐throughput sequencing techniques, with the aim of providing some insight into
novel genomic properties that may illuminate current and future disease associated loci.
Given the base pair resolution approach of high‐throughput sequencing, a novel method of
assaying for SNP effects on gene expression was developed. This allele specific method,
using whole transcriptome sequencing, is capable of identifying alterations in transcript
expression on a genome‐wide scale. | en_US |
