Abstract
Genome-wide association studies have recently identified ten common genetic variants associated with colorectal cancer susceptibility, several suggesting the involvement of components of the transforming growth factor beta (TGFβ) superfamily signalling pathway. To date, no causal sequence variants have been identified, and risk seems to be mediated through effects on gene regulation. Several markers are located close to poorly characterized genes or in gene deserts, raising challenges for elucidating mechanisms of susceptibility. Disease-associated common genetic variation offers the potential to refine risk stratification within populations and enable more targeted disease prevention strategies.
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Acknowledgements
Work that forms the basis of this discussion is supported by Cancer Research UK (C348/A8896, C48/A6361), and the Scottish Executive Chief Scientist's Office (CZB/4/449) — a centre grant from CORE as part of the Digestive Cancer Campaign. We acknowledge those in the Colon Cancer Genetics Group who have contributed to the work reviewed, particularly S. Farrington and H. Campbell, as well as our collaborators R. Houlston and I. Tomlinson and their groups. We thank R. Wilson and N. Cartwright, all of who worked on the COGS and SOCCS administrative teams, R. Cetnarskyj and the research nurse teams who recruited in Scotland, and all clinicians throughout Scotland at collaborating centres. We acknowledge N. Wray and P. Visscher for comments on BOX 1 and for sharing unpublished data on prediction models of genetic risk.
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Glossary
- Excess familial risk
-
The increased risk of developing the disease in a relative of an affected individual. It is usually, and more appropriately, referred to for a specific type of relative. For example, the full-sibling relative risk (s) is the increased risk of developing a disease for a full sibling of an affected person compared with the risk of a person from the general population.
- Heritability
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The proportion of phenotypic variance that is explained by inherited genetic factors.
- Liability scale
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The assumed and unobserved normally distributed risk scale. In the case of a disease, those individuals with a liability score above a specific threshold will have the disease.
- Observed scale
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For a disease trait, the observed scale of the phenotype is either disease or non-disease. The heritability in the observed scale depends on the disease prevalence.
- Odds ratio
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A measure of the effect size. It is the odds of exposure (that is, a specific allele) among the cases divided by the odds of exposure among the controls. In casecontrol studies, the odds ratio is used as an approximation to the relative risk.
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Tenesa, A., Dunlop, M. New insights into the aetiology of colorectal cancer from genome-wide association studies. Nat Rev Genet 10, 353–358 (2009). https://doi.org/10.1038/nrg2574
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DOI: https://doi.org/10.1038/nrg2574
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