West, S.L.; (2011) The search for genetic variants that influence the risk of colorectal cancer. Doctoral thesis , UCL (University College London).

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Abstract

The main aim of this thesis was to uncover common low penetrance variants that influence susceptibility to colorectal cancer (CRC). This was largely considered in relation to the analysis of the plethora of genetic data from our large genome‐wide association study. My work includes fine‐mapping of associated loci through additional genotyping, gene screening, and imputation for the prediction of untyped SNPs, which improved the resolution for fine-mapping and facilitated meta-analysis with datasets typed on different arrays. This led to the identification of 14 independent risk loci, while an association analysis of the X chromosome revealed evidence for two additional risk variants. I cover the detection of runs of homozygous SNPs to investigate the relationship between homozygosity and CRC and show that there is no evidence for increased homozygosity in cases in the UK population. I go on to investigate linkage based techniques to perform an analysis of chromosomal regions identical by descent (IBD), which are shared between unrelated cases more often than controls that could harbour risk variants and identified a number of good candidate genes, such as AXIN2 and E2F7, which require further analysis in additional samples. I also search for moderate penetrance susceptibility variants in several families with a dominant‐like inheritance and compare identified linkage peaks with the results of a loss of heterozygosity analysis of tumour DNA from family members to identify potential tumour suppressor genes. This analysis identified several promising regions and led to the detection of a SMAD4 mutation in one family. The associated variants identified in this study provide good evidence that the common‐disease common-variant hypothesis holds true, but that this is not the whole story as these variants account for just 8% of the familial risk. Further research and techniques will be required to uncover the remaining missing heritability.

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